Benzobicycloalkane amines for inducing analgesia

ABSTRACT

BENZOBICYCLOALKANE AMINES, THEIR PHARMACOLOGICALLY ACCEPTABLE ADDITION SALTS, INTERMEDIATES THEREFORE AND PROCESSES FOR THEIR PREPARATION AND USE. THE COMPOUNDS OF THE INVENTION EXERT ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY.

United States Patent 3,836,670 BENZOBICYCLOALKAN E AMINES FOR INDUCINGANALGESIA Meier E. Freed, Paoli, and John R. Potoski, Spring City,

Pa., assignors to American Home Products Corporation, New York, N.Y. NoDrawing. Continuation-impart of application Ser. No.

200,517, Nov. 19, 1971, which is a continuation-inpart of applicationSer. No. 94,983, Dec. 3, 1970, both now abandoned. This application June14, 1972, Ser.

Int. Cl. A61k 27/00 Us. Cl. 424-330 8 Claims ABSTRACT OF THE DISCLOSUREBenzobicycloalkane amines, their pharmacologically acceptable additionsalts, intermediates therefore and processes for their preparation anduse. The compounds of the invention exert analgesic andanti-inflammatory activity.

CROSS-REFERENCE TO COPENDING APPLICATIONS This application is acontinuation-in-part of copending application Ser. No. 200,517, filedNov. 19, 1971, now abandoned, which is a continuation-in-part ofcopending application Ser. No. 94,983, filed Dec. 3, 1970, nowabancloned.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The inventionsought to be patented in a principal composition of matter aspectresides in the concept of a chemical compound having the structurerepresented by Fortnula I,

wherein R is hydrogen, lower alkyl, lower alkyloxy, hydroxy, acyloxy,phen(lower)alkyloxy, halogen, or tritluoromethyl; R is lower alkyl,lower alkenyl, or phen- (lower)alkyl; R is hydrogen, lower alkyl, orphen(lower) alkyl; R is hydrogen, lower alkyl, phen(lower)alkyl, loweralkenyl, or alkynyl; and n is an integer from 2 to 6; and thepharmaceutically non-toxic addition salts thereof.

The tangible embodiments of the composition aspect of the inventionpossess the inherent general physical properties in the acid salt formof being high melting, white crystalline solids, substantially solublein water and polar organic solvents such as lower aliphatic alcohols andthe like. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Theaforementioned physical characteristics taken together wtih themicroanalytical data, the nature of the starting materials and the modeof synthesis positively confirm the structures of the compositionssought to be patented.

The tangible embodiments of the principal composition aspect of theinvention possess the inherent applied use characteristics of exertingan analgesic effect in animals as evidenced by standard pharmacologicaltests. The anal gesic activity of the compositions can be demonstratedby following a modification of the test procedure described by DAmourand Smith in Journal of Pharmacology, 72: 74 (1941), an accepted testfor analgesic agents. In this test rats are administered the compoundorally, intraperitoneally or intramuscularly and the time required forresponse to a pain stimulus caused by a high intensity beam of lightshining on the tail measured. The compounds of the invention exhibitanalgesic activity in rats at a dose of from 3.15 mg. to 125 mg. perkilogram of body weight orally and intraperitoneally, and from 0.16 to10.0 mg. per kilogram of body weight intramuscularly.

The invention sought to be patented in a principal process aspect isdescribed as residing in the concept of a sequence of reactionsincluding: introducing by alkylation in the presence of a strong baseinto the 1 position of a 2-tetralone, which is l-alkyl, l-alkenyl, or1-phen(lower) alkyl substituted, an w-halo-, w-lower alkyl sulfonyl-,w-phenylsulfonyb, or w-tetrahydlropyranyloxy-alkyl substituent; ifpresent, hydrolyzing the tetrahydropyranyloxy group and converting theresulting alcohol into a suitable leaving group; treating the w-halo-,w-iOWGl alkyl sulfonyl-, w-phen-sulfonyl compound with strong base toeiIect ring closure; then either reacting the tricyclic ketone directlywith ammonia or an amine at elevated temperature with removal of water,and reducing the intermediate imine to produce an amine embodiment ofthe principal composition aspect; or reacting with hydroxylamine underbasic conditions to form an oxime which is reduced to form a primaryamine embodiment of the principal compositions aspect.

The invention sought to be patented in a subgeneric composition aspectis described as residing in the concept of a chemical compound ofFormula I wherein n is 4, or 5.

The tangible embodiments of said subgeneric composition aspect possessthe inherent applied use characteristic of exerting analgesic efiects inwarm-blooded animals as evidenced by pharmacological evaluation bystandard test procedures.

The invention sought to be patented in a second subgeneric compositionaspect is described as residing in the concept of a chemical compound ofFormula I wherein n is 2 or 3.

The tangible embodiments of said subgeneric composition aspect possessthe use characteristic of exerting analgesic effects in warm-bloodedanimals and in addition possess the use characteristic of exertinganti-inflammatory effects in animals as evidenced by standardpharmacologic tests. The anti-inflammatory activity of the compositioncan be demonstrated by following a test procedure described by Winter etal. in Proceedings 0 the Society of Experimental Biology and Medicine,111:54 (1962) and by Buttle et al. in Nature, 179:629 (1957), agenerally accepted test for anti-inflammatory agents. In this test thecompound is administered orally as a solution or suspension in distilledwater to a group of six'rats. After one hour edema in the pa-w of therats is elicited by injection into the paw of a 1% solution ofcarrageenin. Paw volume is measured immediately and after 3 hours. Theability of the compounds to reduce the volume of the edema so producedwhen compared to a like number of control animals is a measure ofanti-inflammatory 3 activity. The compounds of the invention exhibitantiinflammatory activity in rats at a dose of from 50 mg. to 100 mg.per kilogram of body weight.

The invention sought to be patented in a second principal compositionaspect resides in the concept of a chemical compound having thestructure represented by Formula Ia R 1 R 3 R4 (lu wherein R is asdefined hereinabove; R is lower alkyl,

or phen(lower)-alkyl; R is lower alkyl; R is lower alkyl" and n is aninteger from 2 to 6; and the pharmaceutically non-toxic addition saltsthereof.

The tangible embodiments of said second principal composition aspect ofthe invention possess the inherent general physical properties in theacid salt form of being high melting, white crystalline solids,substantially insoluble in water and polar organic solvents and thelike. EX- amination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Theaforementioned physical characteristics taken together with themicroanalytical data, the nature of the starting materials and the modeof synthesis positively confirm the structures of the compositionssought to be patented. The tangible embodiments of said second principalcomposition aspect of the invention possess the inherent applied usecharacteristics of exerting an analgesic effect in warm-blooded animalsas evidenced by standard pharmacological tests.

The invention sought to be patented in its third composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula II:

wherein R, R and n are as hereinbefore described.

The tangible embodiments of the third composition aspect of theinvention possess the inherent general physical characteristics of beinginsoluble in water but soluble at elevated temperatures in polar organicsolvents such as lower aliphatic alcohols and the like.

' Examination of the compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions sought to be patented.

The tangible embodiments of the third composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula I.

The invention sought to be patented in a fourth composition of matteraspect resides in the concept of a chemical 4 t r F compound having thestructure represented by Formula III: V

III

wherein R, R and n are as hereinbefore described.

The tangible embodiments of the fourth composition of matter aspect ofthe invention possess the inherent general physical characteristic ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di-(lower)alkyl ethers,di-(lower)alkyl ketones, lower aliphatic alcohols, chloroform, and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata con-firming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented. V

The tangible embodiments of the fourth composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates for the preparation of the amines of Formula I.

The invention sought to be patented in a fifth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formul IV:

X Z) nY QJ wherein R, R and n are as hereinbefore described, with theproviso that R is not hydroxyl and Y represents a bromine, chlorine,lower alkyl sulfonyl, phensulfonyl or tetrahydropyranyloxy radical.

The tangible embodiments of the fifth composition of matter aspect ofthe invention possess the inherent general physical characteristics ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di-(lower)alkyl ethers,di-(lower)alkyl ketones, lower aliphatic alcohols,.chloroform and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectrographic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the fifth composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula I.

The invention sought to be patented in a sixth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula V:

wherein R, R R and n are as hereinbefore described.

The tangible embodiments of the sixth composition of matter aspect ofthe invention possess the inherent general physical characteristics inthe acid salt form of being high melting, white crystalline solids,substantially soluble in water and polar organic solvents such as loweraliphatic alcohols and the like. Examination of compounds producedaccording to the hereinafter described process reveals, upon infraredand nuclear magnetic resonance spectroscopic analysis, infrared andnuclear magnetic resonance spectral data confirming the molecularstructure hereinbefore set forth. The aforementioned physicalcharacteristics taken together with the nature of the starting materialsand the mode of synthesis positively confirm the structures of thecompositions sought to be patented.

The tangible embodiments of the sixth composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates in the production of the amines of Formula I.

The invention sought to be patented in a seventh composition of matteraspect resides in the concept of a chemical compound having thestructure represented by T N or N i R is lower alkyl, orphen(lower)alkyl, and when X is wherein X is:

lower alkenyl or hydroxy methyl; and R, R R R R and n are as definedhereinabove, and the pharmaceutically non-toxic addition salt thereof.

The tangible embodiments of said seventh composition of matter aspect ofthe invention possess the inherent general physical properties in theacid salt form of being high melting white crystalline solids,substantially soluble in water and polar organic solvents such as loweraliphatic alcohols and the like. Examination of compounds producedaccording to the hereinafter described process reveals upon infrared andnuclear magnetic resonance spectroscopic analysis, infrared and nuclearmagnetic resonance spectral data confirming the molecular structurehereinbefore set forth. The aforementioned physical characteristicstaken together with the microanalytical data, the nature of the startingmaterials and the mode of synthesis positively confirm the structures ofthe compositions sought to be patented.

The tangible embodiments of the seventh composition aspect of theinvention possess the inherent applied use characteristics of exertingan analygesic effect in warmblooded animals as evidenced by standardpharmacological tests.

The invention sought to be patented in an eighth composition of matteraspect residues in the concept of a chemical compound having thestructure represented by XVII wherein R is hydroxy, alkoxy, or when R isnot alkoxy carbonyl, R R is R or alkoxy carbonyl; and R, R R and n areas defined hereinabove.

The tangible embodiments of said eighth composition of the inventionpossess the inherent general physical characteristics of being insolublein water but soluble at elevated temperatures in polar organic solventssuch as lower aliphatic alcohols and the like.

Examination of the compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions sought to be patented.

The tangible embodiments of the eighth composition aspect of theinvention posses the inherent applied use characteristic of beingintermediates in the production of the amines of Formula XVI.

The invention sought to be patented in a ninth composition aspect of theinvention resides in the concept of a chemical compound having thestructure represented by Formula XVIII XVIII wherein R, R and n are ashereinbefore described.

The tangible embodiments of the ninth composition of matter aspect ofthe invention possess the inherent general physical characteristic ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di-(lower)alkyl ethers,di- (lower)alkyl ketones, lower aliphatic alcohols, chloroform, and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the ninth composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates for the preparation of the amines of Formula XVI.

The invention sought to be patented in a tenth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula XIX:

R )ornmr XIX wherein R, R Y and n are as hereinbefore described, withthe proviso that R is not hydroxyl.

The tangible embodiments of the tenth composition of matter aspect ofthe invention possess the inherent general physical characteristics ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di-(lower)alkyl ethers,di-(lower)alkyl ketones, lower aliphatic alcohols, chloroform and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectrographic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore setforth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the tenth composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula XVI.

The invention sought to be patented in a second process aspect isdescribed as residing in the concept of a process for inducing analgesiain warm-blooded animals by administering to warm-blooded animals, apharmaceutically effective dose of a compound of Formula I, Formula Ia,or Formula XVI.

As used herein the term lower alkyl means a saturated hydrocarbonradical, including the straight and branched radicals having from 1 to 4carbon atoms, amon which are for the purposes of illustration, butwithout limiting the generality of the foregoing, methyl, ethyl,n-propyl, n-butyl, and i-butyl. The term lower alkenyl means anunsaturated hydrocarbon radical, including straight and branchedradicals, having from 3 to 5 carbon atoms, among which are for thepurposes of illustration but Without limiting the generality of theforegoing, allyl, Z-butenyl, 3 methyl 2 butenyl, Z-methyl-Z-butenyl, and2-pentyl. The term lower alkynyl means an unsaturated hydrocarbonradical, containing a triple bond, including straight and branchedradicals, having from 3 to 6 carbon atoms, among which are for thepurposes of illustration, but without limiting the generality of theforegoing 3-propynyl, 2- butynyl, 1 butyn-3-yl, and3-methyl-1-butyn-4-yl. The term phen(lower)alkyl means a lower alkylradical as defined hereinabove substituted in a terminal position by aphenyl or a phenyl radical substituted by lower alkyl or lower alkyloxy,among which are for the purposes of illustration but Without limitingthe generality of the foregoing benzy, phenethyl, 0, m, or p-anisyl, por m-cumenyl, veratryl, o, m, or p-Xylyl. The term phensulfonyl means aphenyl or substituted phenyl sulfonic acid radical among which are, forthe purposes of illustration, but without limiting the generality of theforegoing, phenyl sulfonyl, or p-toluene sulfonyl. The term acyloxymeans either an aliphatic or aromatic carboxylic acid radical; ifaliphatic, it may contain from 2 to 7 carbon atoms either straightchain, branched or concatenated to form a carbocyclic ring, among whichare for the purposes of illustration but without limiting the generalityof the foregoing acetic, propionic, butyric, i-butyric,cyclohexanecarboxylic, cyclopentanecarboxylic; if aromatic, it maycontain an unsubstituted aromatic nucleus or the aromatic nucleus ringsubstiuted by lower alkyl, among which are for the purposes ofillustration but without limiting the generality of the foregoing,benzoic, 0, m, or p-toluic, p or m-ethylbenzoic.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 6, 7,8,9,l0,11 hexahydro3-methoxy-5,IO-methano-SE- benzocyclononen l2-amine (Xa); specifictertiary amine embodiments of Formula I, namely N-allyl-N,5-dimethyl-6,7,8,9,l0,ll hexahydro 3-methoxy-5,IO-methano-SH-benzocyclononen-lZ-amine (XII) and N-allyl-N-ethyl 6, 7,8,9,l0,1lheXahydro-3-methoxy-5-methyl-5,IO-methano SE-benzocyclononen-lZ-amine(XIII); a specific embodiment of Formula II, namely6,7,8,9,10,l1-hexahydro- 3methoxy-S-methyl-S,10-methano-SII-benzocyclononem 12-one, oxirne (IX); aspecific embodiment of Formula III, namely 6,7,8,9,l0,l1hexahydro-3-methoxy-S-methyl-S, 10 rnethano-5E-benzocyclononen-l2-one(VIII); and a specific embodiment of Formula IV, namelyl-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone (VII).

Referring now to Figure A, the starting materials for the invention,l-alkyl, l-alkenyl, or 1-phen(lower)alkyl- 2-tetra1ones, may be preparedfrom commercially available Z-tetralones, by a well-known alkylationreaction as typically described by Stork and Schulenberg in the Journalof the American Chemical Society, 84, 284 (1962). The tetralones aretreated with pyrrolidine in an inert solvent such as benzene, and thenreacted with the appropriate lower alkyl, lower alkenyl, orphen(lower)alkyl halide in an inert solvent, such as benzene or dioxane,at elevated temperatures, conveniently the reflux temperature of thesolvent employed. They may also be prepared from a suitable commerciallyavailable l-tetralone which may be treated as described by Howell andTaylor in the Journal of the Chemical Society, 1958, 1249 with aGrignard reagent, prepared from the appropriate lower alkyl, loweralkenyl, or phen (lower)alkyl halide, and the resultingdl l-substituteddihydro-naphthalene oxidized with perac1 Syntheses of non-commerciallyavailable tetralones are readily available in the literature, eg thesynthesis of atetralone is described in Organic Synthesis, CollectiveVolume IV, page 898; the synthesis of ,B-tetralone is described in thesame work on page 903; and a general synthesis of ,B-tetralones isdescribed in Nagata et al. Netherlands Pat. 6709534, Jan. 10, 1968.

The first step in preparing the aforementioned embodiments is theportionwise addition, in the cold, of a strong base, such as asuspension of sodium hydride in benzene, to a stirred solution of1-methyl-7-methoxy-Z-tetralone (VI) and l bromo-4-chloro-butane, indimethyl formamide, followed by a period of stirring at roomtemperature, to produce compound VII. Compound VII is converted to thebridged tetralone VIII by treatment with a strong base, preferablysodium hydride, in an inert solvent, preferably dimethyl formamide. Thebridged tetralone VIII so produced is then used as an intermediateeither for the production of the oxime IX or if desired for theproduction of the secondary amine Xa.

FIGURE A H3O ct-ncincmornol 11.00- 0 BMCHZ) 4C1 H300 o NaH VI VII 9FIGURE A-Continued l q l H C H C moo ""NHQ H.c Nncm/ XI Xa ong onomnrH300 I NIICIIQCHZCHQ XI X l HB r H3 0 1. C l C OzEt 2. LAH

H O NH2 1 CH3 C OCl XIV 2 LAH H36 1. Carbobenzoxy CH CH=CH chloride 2.Acetic anhy- I-I- CO N dlide 3. Reduction CH H C XII H3 C (50 NHz 3cmon=cm In order to prepare the oxime IX the bridged tetralone VIII istreated with hydroxylamine under basic conditions.

mary amine XI. To prepare the amine XI the oxime IX is treated eitherwith hydrogen in the presence of a catalyst, preferably Raney nickel,and ammonium hydroxide,

at moderate pressure, preferably 40-50 p.s.i.; the hydride reducingagents, for example lithium aluminum hydride; diborane at elevatedtemperature; or an alkali metal, preferably sodium, in an alkanol, forexample ethanol or isopropanol. When using catalytic reduction thereaction proceeds stepwise and the corresponding imine of Formula V maybe isolated as an intermediate, and then may be reduced to the desiredprimary amine. The amine XI is isolated by conventional means. Toprepare the amine Xa, the bridged tetralone VIII is treated with anexcess of methyl amine. The substitution is carried out with removal ofwater, conveniently in the presence of calcium oxide, at an elevatedtemperature, preferably 180-190 C. When the amine has a boiling pointbelow the desired temperature the reaction is conveniently carried outin a sealed pressure vessel. The intermediate imine so produced may bereduced as obtained directly from the substitution reaction. The aminoXa is produced by treating this irnine with either hydrogen in thepresence of a catalyst, preferably platinum oxide, at moderate pressure,preferably 40-50 p.s.i.; the hydride reducing agents, for examplelithium aluminum hydride or sodium borohydride; diborane at elevatedtemperature, or an alkali metal, preferably sodium, in an alkanol, forexample ethanol or isopropanol. The primary amine X I may also beconverted to the secondary amine X by substitution reactions well knownin the art of organic chemistry. A convenient method is to treat withone mole equivalent of allyl bromide. The substitution is carried out inthe presence of an organic acid acceptor, preferably di-isopropyl ethylamine, in an organic solvent at a temperature of from about 60 C. to C.Benzene and xylene are particularly useful solvents but it will beapparent to an organic chemist that any solvent can be used which willnot interfere with the course of the reaction. For convenience thereflux temperature of the solvent selected can be employed. Thesecondary amine X is isolated by conventional methods.

If desired the secondary amine X can be methylated to give the N-methyltertiary amine XIL A preferred method for the methylation reaction is tofirst carbethoxylate the secondary amine by treatment with ethylchloroformate in an unreactive organic solvent, such as methylenechloride or chloroform. For best results, a weak inorganic base, such assodium bicarbonate or potassium carbonate, is added to the reactionmixture. The temperature of the carbethoxylation reaction is notcritical and, for convenience, room temperature is used. It will beobvious to one skilled in organic chemistry that for the purposes ofthis reaction other halo formate esters would be equivalent to ethylchloroformate. The carbethoxylated amine is then reacted with a reducingagent, preferably lithium aluminum hydride, in an inert solvent,preferably ether or tetrahydrofuran, to afford the N-methyl tertiaryamine XII which is isolated by standard procedures.

A preferred method of preparation of the tertiary amine XIII is to firstacylate the secondary amine X with acetyl chloride in a basic organicsolvent, preferably pyridine, at an elevated temperature, convenientlythe reflux temperature of the solvent selected. The acylated amine isthen reacted with a reducing agent, preferably lithium aluminum hydride,in an inert solvent preferably ether or tetrahydrofuran, to afford thetertiary amine XIII which is isolated by standard techniques.

The primary amine XI which bears a lower alkyloxy substituent can behydrolyzed to the phenolic compound XIV. A particularly useful method isto treat the primary amine with 48% aqueous hydrobromic acid at elevatedtemperature, conveniently reflux temperature. The crystalline product isisolated by standard techniques. It will be obvious to one skilled inthe art of organic chemistry that the hydrolysis reaction may beperformed on the bridged tetralone VIII and that the phenolic compoundsoformed would then be the full equivalent of all other compounds notbearing such a substituent in all subsequent reactions.

The phenolic amine XIV may be acetylated to produce the acetylderivative XV. A skilled organic chemist will recognize that in order toacetylate the phenolic function a primary or secondary amine must firstbe reacted with a suitable protecting group. Carbobenzoxy chloride isparticularly convenient for this purpose. The protected derivative isthen treated with acetic anhydride and the protecting group removed,conveniently, in the case of the carbobenzoxy group by hydrogenolysis.It Will be obvious to a skilled organic chemist that any desiredacylation reagent may be substituted for the acetic anhydride. Theacylation reaction may also be accomplished by exposure of the phenolicamine, suitably distributed on an inert carrier, conveniently potassiumbromide powder, to a suitably volatile acylating agent, in the vaporstate, at tem- 1 l peratures moderately higher than room temperature,conveniently 40-70 C.

While the processes of the invention have been specifically describedwith reference to the drawing which illustrates their application tol-methyl-7-methoxy-2-tetralone it will be readily apparent to oneskilled in the art of organic chemistry that the processes will beequally applicable to tetralones bearing, in the 1 and 7 positions,other substituents contemplated within the scope of the invention.Similarly it will be obvious to vary the chain length of thepolymethylene compound in order to produce the variously sized ringsystems encompassed by the invention. A skilled chemist will readilyrecognize that, in addition to the a,w-dihalopolymethylene, anypolymethylene compound of the desired chain length, which bears, assubstituents in the terminal positions, suitable leaving groups, such as(lower) alkylsulfonyl or phensulfonyl, or one such leaving group and agroup, such as tetrahydropyranyloxy which may be readily converted to aleaving group, may be utilized in the initial cycloalkylation process.The substitution of other strong bases, such as alkali metal alkoxides,in suitable solvents, for the illustrated sodium hydride will also beapparent to one skilled in the art. It will be obvious to one skilled inthe art that, if the a,w-disubstituted polymethylene does not bear atetrahydropyranyl substituent, the complete cycloalkylation may beperformed Without isolation of the intermediate, compound VII. Oneskilled in the art will recognize that it is possible to substituteanhydrous ammonia for methyl amine in the imination of compound VIII andthat reduction will then give compound XI. The substitution of otherlower alkyl, and phen(lower)alkyl amines, for methylamine, to givesecondary amines analogous to compound Xa will similarly be ap arent toone skilled in the art. Other lower alkyl halides, lower alkenylhalides, phen (lower)alkyl halides, or lower alkynyl halides may besubstituted for allyl bromide in the treatment of compound XI to obtainthe secondary amines encompassed by the invention. Similarly other loweralkanoyl, lower alkenoyl, phen(lower)alkanoyl or lower alkynyl halidesmay be used in the preparation of the tertiary amine embodiments of theinvention.

The amine oxides of Formula Ia are prepared by oxidation, convenientlywith an organic peracid, of the di- (lower)alkyl tertiary amineembodiments of Formula I.

One knowledgeable in the art of organic chemistry will recognize thatl-alkyl substituted 2-indanones and 2- benzsuberones can becycloalkylated in a fashion similar to that described for thecycloalkylation of 1-alkyl substituted 2-tetralones. The compounds canthen be further treated by the processes described hereinabove toproduce derivatives which are the full equivalents of the compounds ofFormula I described herein.

The substituted tetralones described hereinabove and their equivalentindanone and benzsuberone analogous may be substituted at various otherpositions on the aromatic ring with such radicals as lower alkyl, loweralkyloxy, halo and trifiuoromethyl and these may be employed as startingmaterials in the initial cycloalkylation reactions and such compoundscan then be treated by the processes described hereinabove, to produceamino derivatives bearing these variously located substituents.

Preparation of the indanones of Formula XVI may also be accomplished bycyclization of appropriate known o-phenylene diacetic acid diesters toproduce l-alkoxycarbonyl-Z-indanones. Alkylation to produce the l-alkoxycarbonyl-indanones of Formula XIX may be accomplished by standardalkylation techniques. Alternatively the keto group of the alkoxycarbonylindanone may be treated with a suitable ketone protectingreagent, such as ethylene glycol, a lower alkyl, lower alkenyl, or phen-(lower)alkyl group may be introduced into the 1-position by standardalkylation techniques, the protective group removed from the ketone, theester function hydrolyzed, and the carbonyl group eliminated bydecarboxylation. The resulting lower alkyl, lower alkenyl, orphen(lower) alkyl-Z-indanone may then be treated similarly to thecorresponding tetralones to produce the lower alkyl, lower alkenyl orphen(lower)alkyl indanones of Formula XIX. Cycloalkylation to thebenzobicyclic system of Formula XVIII may be accomplished as describedfor the corresponding tetralones of Formula IX. Preparation Of the iminoderivatives of the benzobicyclic ketones derived from the abovedescribed indanones may be accomplished in a fashion similar to thatdescribed for the preparation of the imino derivatives of thebenzobicyclic ketones derived from tetralones. A skilled organic chemistwill of course recognize that the alkoxy carbonyl Substitutedbenzobicyclic ketones may be converted to oximino derivatives but thattreatment with ammonia or primary amine will result in side reactionswith the alkoxy carbonyl group.

The skilled organic chemist will of course not use catalytic reductionmethods involving the use of ammonia or primary amines.

The alkoxy carbonyl benzobicyclic ketone may, if de sired, be treatedwith a suitable ketone protecting reagent, such as ethylene glycol, andalkoxy carbonyl group may then be reduced to a hydroxy methyl group, andthe keto group regenerated. This compound may then be converted into thehydroxy methyl imino compounds of Formula XVII by the above describedmethods.

Reduction of the oximes or imines of Formula XVII to the amines ofFormula XVI may be accomplished by the same reduction methods as used toprepare the amines of Formula I. Those embodiments of Formula XVIIcontaining an alkoxycarbonyl will, of course, simultaneously beconverted to the embodiments of Formula XVI which have ahydroxy(lower)a1kyl substituent. If desired the hydroxyl group may beremoved by standard means, such as tosylation and reduction with lithiumaluminum hydride. Ordinarily this process will result in an N-tosylamine from which the free amine may be recovered by hydrolysis. Thevariously other substituted amines of Formula XVI may be prepared fromappropriate primary or secondary amines or embodiments of Formula XVI byprocesses similar to those described for the preparation of thevariously substituted amines of Formula I.

It will be obvious to one skilled in the art of chemistry that thebenzobicyclic ketones of Formula III and Formula XVIII will be producedas racemic mixtures, and that reduction of either oximes of Formula IIand Formula XVII or imines of Formula V and Formula XVII will yield theamines of Formula I and Formula XVI as diasteromers. The separation ofthe diastereorneric pairs and their resolution into enantiomers, ifdesired, may be accomplished by well-known procedures. Thediastereomers, enantiomers and mixtures thereof are all included withinthe scope of this invention.

It is convenient in the present application to distinguish pairs ofdiastereomers by specifying the orientation of the amino group. A numberof conventional systems of nomenclature for specifying the orientationare'suitable, and selection of a particular system is a matter ofconvenience. Because of its greater specificity and more generalapplicability, a system enabling specification of the relativeorientation of all substituents on the Tetralin ring system has beenadopted for use in this application. In this system the Tetralin ring isprojected on a plane. Those substituents extending below the plane aredesignated a, and those extending above the plane are designated [3.

In the process for the use of the amines of Formula I and Formula XVI orpharmaceutical acceptable salts thereof, they may, if desired, beformulated with pharmaceutically acceptable carriers in accordance withmethods well-known in the art.

It will be obvious to those skilled in the art that N- oxides of thedialkyl substituted tertiary amines of Formula XVI may be prepared in afashion similar to that described for the preparation of the N-oxides ofFormula Ia. These N-oxides are the full equivalents of those embodimentsof the invention specifically described.

of the formula:

R -NH2 Hun-1 wherein R, R and It are as defined hereinabove; and m is or1, as described by Wiesner, Chan and Demerson in Tetrahedron Letters,1965, page 2893, followed by either dehydration and hydrogenation of theresulting double bond, or tosylation and cleavage of the tosyl group.This route is the preferred method of synthesis for those embodimentswherein n is 2 or 6.

The tangible embodiments of the principal composition aspect have beenfound to possess the additional applied use characteristic of exertingmorphine antagonism effects in animals when tested in standardpharmacological eval uation procedures. The morphine antagonism effectscan be demonstrated by administering the compound to morphine addictedmonkeys. A morphine antagonist precipitates morphine withdrawalsymptoms. The morphine antagonism efiect can also be demonstrated bydosing groups of three male Charles River rats subcutaneously withmorphine at 75 mg./kg. of base. The degree of narcosis induced by themorphine is measured at and minutes after injection. Criteria are lossof righting reflex, tail and body rigidity and respiratory depression.Test compounds are administered intramuscularly, minutes after themorphine. The degree of antagonism is measured at 20 minute intervalsfor 2 hours. Nalorphine, at 2 mg./kg., serves as a positive controlwhile one group of morphinized rats in each determination receives noantagonist and serves as negative controls. Reversal of the loss ofrighting reflex constitutes a positive response.

The following examples illustrate the best mode contemplated by theinventors for preparing the compositions of the invention.

EXAMPLE I 1- (4-Chlorobutyl -1-Methyl-7Methoxy-Z-Tetralone 1Methyl-7-methoxy-2-tetralone (57 g.), tetramethylene chlorobromide (200g.) and dimethyl formamide (250 ml.) are introduced into a two literreaction vessel which is fitted with a condenser and drying tube, amechanical stirrer, a nitrogen inlet, a thermometer, and a soft rubberstopper. After this solution is cooled to 10 C. a suspension of sodiumhydride (approximately 8 g. freed of mineral oil by washing withbenzene) in benzene (100 ml.) is added slowly in 10 ml. portions,through the rubber stopper with the aid of a syringe. The temperature ismaintained between 12 and 20 for the 1.5 hour addition period. Thereaction is then allowed to warm to room temperature, stirred for 3 /2hours, and poured into ice water (1.5 1.). The layers are separated, theaqueous phase extracted with ether, the combined organic phases washedwith saturated saline, dried over sodium sulfate and the organicsolvents removed under reduced pressure. Distillation of the residueyields the title product (62.5 g.), b.p. l55185 C. (approximately 0.3mm.).

LR. analysis: 585, 7.95

EXAMPLE II 1-(3-Bromopropyl)-1-Methyl-2-Tetralone Sodium hydride (0.75g.) washed free of mineral oil is added in smallportions, over a periodof minutes, to a well stirred solution of l-methyl-2-tetralone (4.8 g.)and 1,3-dibromopropane (24 g.) in benzene (100 ml.) while maintainingthe temperature at 25 C. The mixture is stirred at room temperature for1 hour and heated at reflux for 2 hours. When cool 2 drops of aceticacid are added and the mixture clarified by filtration throughdiatomaceous earth. Concentration of the filtrate and distilla- 14 tionof the resulting residue gives the title product (4.5 g.), b.p. l35 C.(0.1 mm); 2,4-dinitrophenyl hydrazone, m.p. 146148 C.

Analysis-Calculated for C H N O Br: C, 52.07; H, 4.59; N, 12.14; Br,17.32. Found: C, 51.87; H, 4.64; N, 11.97; Br, 17.12.

EXAMPLE III 1- 3-Bromopropyl -1-Methyl-7-Methoxy-2-Tetralone Using aprocedure analogous to that described in Example II for the preparationof l-(3-bromopropyl-1- methyl)-2-tetralone there is obtained froml-methyl-7- methoxy-2-tetralone (11.4 g.) and 1,3-dibromopropane (24ml.), 6.7 g. of the title product, b.p. -145 C. (1 mm.).

LR. analysis: 5.8, 8.0a.

EXAMPLE IV 1-(5-Bromopentyl)-1-Methyl-2-Tetralone Using a procedureanalogous to that described in Example I for the preparation of1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there is obtained froml-methyl- Z-tetralone (20.0 g., 0.125 mole), 1,5-dibromopentane (115.0g., 0.5 mole), and sodium hydride (6.06 g., 0.1375 mole of a 54.5%dispersion in mineral oil) in dimethylformamide (100 ml.), 19.8 g. (54%)of the title product, b.p. -175 C. (0.3 mm.).

I.R. analysis: 3.45, 585a.

EXAMPLE V 1-(5-Bromopentyl)-1-Methyl-7-Methoxy-2-Tetralone Using aprocedure analogous to that described in Ex ample I for the preparationof 1-(4-ch1orobutyl)1methyl-7-methoxy-2-tetralone there is obtained froml-methyl- 7-methoxy-2-tetralone (150.0 g., 0.788 mole),1,5dibromopentane (707 g., 3.06 mole), and sodium hydride (37.1 g.,0.842 mole of a 54.5% dispersion in mineral oil) in dimethylformamide(600 ml.), 182 g. (68.1%) of the title product, b.p. 185l98 C. (1.0mm.).

LR. analysis: 3.5, 5.80, 7.911..

EXAMPLE VI 1-(4-Chlorobutyl)-1-Ethyl-7-Methoxy-2-Tetralone (A) Using aprocedure analogous to that described in Example I for the preparationof 1-(4-chlorobutyl) 1- methyl-7-methoxy-2-tetralone there is obtainedfrom 35 g. of 1-ethyl-7-methoxy-2-tetralone; 37.4 g. of the titleproduct, b.p. -173 C. (0.4 mm.).

LR. analysis: 5.83, 8.011.

(B) Clean sodium pellets (2.3 g.) are dissolved, while stirringmagnetically under N in absolute ethanol (50 ml.). After cooling to 2025C. 1-ethyl-7methoxy-2- tetralone (20.5 g.) in dry ethanol (50 ml.) isadded over a period of 30 minutes. After stirring 30 minutes thissolution is added dropwise to a stirred solution of 1,4-dibromobutane(44.0 g.) in dry ethanol (60 ml.) while maintaining the temperature at10-15 C. After stirring four hours at this temperature the reaction isallowed to warm to 20-25 C. while continuing to stir an additional .12hours. After chilling below room temperature precipitated solids areremoved by filtration with the aid of diatoma ceous earth. Concentrationof the filtrate under reduced pressure, partitioning the residue soobtained between ether and water, washing the ether layer with saline,drying, concentrating under reduced pressure and distilling under vacuumgives the title product (16 g.), b.p. (0.2 mm.). 1

EXAMPLE VII 1- (4-Chlorobutyl -1-Methyl-5-Methoxy-2-Tetralbne Using aprocedure analogous to that described in Example I for the preparationof1-(4-chlorobutyl)-l-methyl-7-methoxy-2-tetralone there is obtainedfrom 1-methyl- 5-methoxy-2-tetralone (45 g.), 40.5 g. of the titleproduct, b.p.150-l60 C. (0.15 mm.).

LR. analysis: 5.82, 7.911..

1 5 EXAMPLE VIII 1-(4-Chlorobutyl)-1-Methyl-6-Methoxy-2-Tetralone Usinga procedure analogous to that described in EX- ample I for thepreparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there isobtained from l-methyl- 6-rnethoxy-2-tetralone (36 g.) andtetramethylene chlorobromide (140 g.), 30.5 g. of the title product,b.p. 165- 175 C. (0.4 mm.).

LR. analysis: 5.85, 8.0 4.

EXAMPLE IX To prepare: l-benzyl-1-(4-ch1orobutyl)-2-tetralone react1-benZyl-2-tetralone with 1-bromo-4-chlorobutane as taught in ExampleI.-

To prepare: lbenzyl-1-(4-chlorobutyl)-7-methoxy-2- tetralone react1-benzyl-7-methoxy-2-tetralone with 1- bromo-4-chlorobutane as taught inExample I.

EXAMPLE X 6,7,8,9,10,11-Hexahydro-3-Methoxy-S-Methyl-5,l0-Methano-SH-Benzocyclononen-12-One To a two liter reaction vessel, fittedwith a mechanical stirrer, a dropping funnel, a condenser and dryingtube, a thermometer, a nitrogen inlet and a soft rubber stopper isintroduced sodium hydride (13 g., 0.27 mole of 50% dispersion in mineraloil) which is then washed with benzene to remove the mineral oil.Dimethylformamide (750 ml.) is then added and1-(4-chlorobutyl)-l-methyl-7- methoxy-Z-tetralone (62.5 g., 0.22 mole)in dimethyl formamide (150 ml.) is added dropwise, while stirringvigorously and maintaining the temperature between 30 and 35 C. Thereaction is stirred and heated to 80 to 85 C. for 2.5 hours, stirred atroom temperature overnight and poured into ice water (2.0 liter). Afteracidification with hydrochloride acid (concentrated) the oil whichseparates is extracted into ether. The extract is washed with saturatedsaline and dried over sodium sulfate. The solvent is removed underreduced pressure and the residue distilled to give the title product(32.5 g.), b.p. 130 to 135 C. (0.25 mm.).

I.R. analysis: 5.8, 8.0

EXAMPLE XI 5,6,7,8,9,10-Hexahydro-3-Methoxy-5-Methyl-5,9-Methano-Benzocycloocten-1l-One Using a procedure analogous to thatdescribed in Example X for the preparation of 6,7,8,9,10,l1-hexahydro-3-methoxy-S-methyl-S,10-methano-5g-benzocycloocten 12- one there isobtained from 1-(3-bromopropyl)-1-methyl- 7-methoxy-2-tetralone in 74%yield the title product, b.p. 118 to 121 C. (0.05 mm.). A sample isconverted to the semicarbazone, m.p. 223 to 225 C.

Analysis.Calculated for C H N O C, 66.87; H, 7.37; N, 14.62. Found: C,66.73; H, 7.51; N, 14.74.

EXAMPLE XII 5,6,7,8,9,10-HeXahydro-5-Methy1-5,9 Methanobenzocycloocten-l1-One EXAMPLE XIII 5-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,1l-Methano-Benzocyclodecen-13-One (A) Using a procedure analogous to that describedin Example X for the preparation of 6,7,8,9,10,11-hexahydro- 3-methoxy 5methyl 5,10 methano-SE-benzocyclononen-12-one there is prepared froml-methyl-l-(S-bromopentyl)-2-tetralone (19.8 g., 0.0675 mole) and sodiumhydride (3.57 g., 0.081 mole, of a 54.5% dispersion in mineral oil) indimethylformamide (250 ml.) 6.2 g. (40.4%) of the title product, b.p.126 to C. (0.3 mm.).

I.R. analysis: 3.45, 5.9,u.

(B) Oil-free sodium hydride (5.28 g.) in benzene (50 ml.) is added to astirred mixture of 1,5-dibromopentane (184 g.) and1-methyl-7-methoxy-Z-tetralone (32 g.) in dry benzene (300 ml.).Stirring is continued for 12 hours at 25 and at reflux for an additional15 hours. The mixture is cooled, sodium hydride (5.8 g.) in 50 ml.benzene added, stirring continued at 25 for 10 hours, and at reflux for12 additional hours. After cooling excess base is neutralized withconcentrated hydrochloric acid and the inorganic solids whichprecipitate are removed by filtration. Washing the filtrate with saline,drying over sodium sulfate, concentrating and vacuum distilling gives anoil (21 g.), b.p. 160-190 C. (0.5 mm.) containing 6.5 g. (27%) of thetitle product by vapor phase chromatography (3% OVI, C200225250).

EXAMPLE XIV S-Methyl-3-Methoxy-5,6,7,8,9,10,11,12-Octahydro-5,11-

Methano-Benzocyclodecen-13-One Using a procedure analogous to thatdescribed in Example X for the preparation of 6,7,8,9,10,11-hexahydro- 3methoxy 5 methyl-5,10-methano-SIi-benzocyclononen-12-one there isobtained from 1-methyl-1-(5-bromopentyl)-7-m-ethoxytetralone (90.0 g.,0.265 mole), and sodium hydride (12.87 g., 0.292 mole, of 54.5%dispersion in mineral oil) in dimethylformamide (750 ml.); 42.7 g.(62.4%) of the title product, b.p. 150 to 175 C. (0.5 mm.).

LR. analysis: 3.0, 3.4, 5.9, 8.01,.

EXAMPLE XV 6,7,8,9,10,l 1-Hexahydro-2-Methoxy-5-Methyl-5,10- Methano-S I1 -Benzocyclononen- 1 2-One Using a procedure analogous to thatdescribed in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy 5 methyl-5,10-methano-SE-benzocyclononen- 12-one, there isobtained from 30.5 g. of1-(4-chlorobutyl)-1-methyl-6-methoxy-2-tetralone 15 g. of the titleproduct, b.p. to C. (0.5 mm.).

LR. analysis: 5.82, 8.05;.

EXAMPLE XVI 6,7, 8,9,10,1l-Hexahydro-l-Methoxy-S-Methyl-S,l0-Methano-SE-Benzocyclononen-12-One Using a procedure analogous to thatdescribed in Example X for the preparation of 6,7,8,9,10,11-hexahydro 3-methoxy-S-methyl 5,10 methano-SE-benzocyclononen- 12-one, there isobtained from 40.5 g. of1-(4-chlorobutyl)-1-methyl-5-methoxy-2-tetralone, 21.5 g. of the titleproduct, b.p. 130 to 135 C. (0.3 mm.).

I.R. analysis: 5.78, 7.9,u.

EXAMPLE XVII 5-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,l0-Methano-Sg-Benzocyclononen-12-One Using a procedure analogous to thatdescribed in Example X for the preparation of 6,7,8,9,10,11-hexahydro- 3methoxy 5 methyl 5,10 methano SE-benzocyclonen 12-one there is obtainedfrom 37.4 g. of 1 (4 chlorobutyl)-1-ethyl-7-methoxy-2-tetralone, 22.2 g.of the title product, b.p. 138 to 142 C. (0.35 mm.).

I.R. analysis: 5.85, 8.0

EXAMPLE XVIII To prepare: 6,7,8,9,10,1l hexahydro 5-benzyl-5,10-methano-SE-benzocyclononen-12-one, treat l-benzyl-l- 1'7(4-chlorobutyl)-2-tetralone with taught in Example X.

To prepare:-benzyl-3-methoxy-6,7,8,9,10,ll-hexahydro-S,lO-methano-Sg-benzocyclononen-l2-one,treat 1- benzyl 1 (4-chlorobutyl)-7-methoxy-2-tetralone with sodiumhydride as taught in Example X.

EXAMPLE XIX 6,7,8 ,9,10, l l-HeXahydro-3 -Methoxy-5-Methyl-5-10-Methanodg-Benzocyclononen-12-One, Oxime (A) 6,7,8,9,10,11 Hexahydro 3methoXy-5-methyl- 5,10 methano 5g benzocycononen-12-one (0.2 g.),hydroxylamine hydrochloride (0.5 g.) 5% sodium hydroxide (6 ml.) andethanol (2 ml.) are heated at reflux for 4 hours. The reaction is cooledand diluted with Water. The supernatant is decanted from the oil whichseparates. The oil is Washed several times with water and is thentreated with 2-propanol from which the title product crystallizes, m.p.174 to 176 C.

AI1alysis.-Calculated for C H NO C, 74.1; H, 8.16; N, 5.40. Found: C,74.38; H, 8.10; N, 4.98.

IR. analysis: 3.2, 6.2, 8.1a.

(B) Hydroxylamine hydrochloride (14 g., 0.2 mole) in methanol (250 ml.)is mixed with sodium acetate (165 g., 0.2 mole) is methanol (200 ml.).After standing one hour this solution is filtered and to it is added6,7,8,9, 10,11 hexahydro 3 methoxy-5-methyl-5,10-methano-SH-benzocylononen-12-one (10 g., 0.04 mole). The soluti n is heatedunder reflux 5 hours, concentrated in volume to approximately 200 ml.Cooling, filtration, Washing with methanol and drying gives the titleproduct (8.0), m.p. 174 to 176 C.

(C) 6,7,8,9,l0,11 Hexahydro 3 methoxy-S-methyl- 5,10 methano 5gbenzocyclononen-lZ-one (20.0 g., 0.082 mole), and hydroxylaminehydrochloride (28.5 g., 0.410 mole) in pyridine (150 ml.) are stirred atreflux for 24 hours. The mixture is cooled and concentrated. The residueis extracted with ether (750 ml.) in several portions and the extractsare successively Washed with water, dilute hydrochloric acid, Water andsaline solution, then dried over anhydrous magnesium sulfate, thesolvent removed in vacuo and the residue crystallized from boilingisopropanol to give the title product (6.0 g), m.p. 167 to 171 C. Asecond crop Was obtained, 1.08 g. Total yield is 33%.

sodium hydride as EXAMPLE XX 5 -Methyl-5 ,6,7,8,9,10,1 1,12-Octahydro-5,1 l-Methano- Benzocyclodecen-I 3-One, Oxime Using a procedure analogousto that described in Example XIX, Method (C), for the preparation of6,7,8,9,10,11 hexahydro 3 methoxy-5-methyl-5,10- methano 5Ebenzocyclononen-lZ-one, oxime there is obtained from 5 methyl5,6,7,8,9,10,11,12-octahydro- 5,11 methano benzocyclodecen-lS-one (3.9g., 0.0171 mole) and hydroxylamine hydrochloride (8.55 g., 0.123 moles)in pyridine (20 ml.), after recrystallization from isopropanol, 1.27 g.of the title product, m.p. 122-127.

LR. analysis: 3.15, 3.45, 6.1,u.

EXAMPLE XXI 5 ,6,7,8,9, 10-Hexahydro-3-Methoxy-5 -Methyl-5 ,9-Methano-Benzocycloocten-1l-One, Oxime By a procedure analogous to thatdescribed in Example XIX, Method (A), for the preparation of6,7,8,9,10,11- hexahydro 3 rnethoxy 5 methyl-5,10-methano-5E-benzocyclononen-12-one, oximed there is obtained from 5,6,7,8,9,10hexahydro 3 methoxy 5-methyl-5,9- methanobenzocycloocten-l1-one (0.5 g.)and hydroxylamine hydrochloride (6.5 g.), 3.9 g. of product aftertrituration with hexane, m.p. 138-142 C. Recrystallization fromisopropanol-water gives the title product, mp. 146-148" C.

Analysis.-Calculated for C H NO C, 73.44; H, 7.81; N, 5.71. Found: C,73.11; H, 8.03; N, 5.61.

18 EXAMPLE XXII 5-Methyl-3-Me-thoxy-5,6,7,8,9,10,11,12-Octahydro-5,11-

Methano-Benzocyclodecen-13-One, Oxime Using a procedure analogous tothat described in Example XIX, Method (C), for the preparation of6,7,8,9,10,11 hexahydro 3 methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one, oximed there is obtained from 5methyl 5,6,7,8,9,10,11-octahydro-5,11- methano-benzocyclodecen-l3-one(42.6 g., 0.165 mole), and hydroxylamine hydrochloride (57.3 g., 0.824mole) in pyridine (300 ml.); 18.9 g. (42%) of the title product, m.p.152158 C.

Analysis.-Calculated for C H N O C, 74.69; H, 8.48; N, 5.12. Found: C,75.25; H, 8.64; N, 4.72.

EXAMPLE XXIII 6,7 ,8,9, 10-Hexahydro-Z-Methoxy-S-Methyl-S 1 0-Methano-SIi-Benzocyclononen-12-One, Oxime Using a procedure analogous tothat described in Example XIX, Method (B), for the preparation of6,7,8,9,10,11 hexahydro 3 methoxy 5 methyl-5,10-methano-Sg-benzocyclononen-12-one, oxime there is obtained from 11.5 g.of 6,7,8,9,10,11hexahydro-2-methoxy 5 methyl5,10-methano-5g-benzocyclononen- 12-one (5.0 g.) of the title product,m.p. -135 C.

LR. analysis: 3.1; 6.0

EXAMPLE XXIV 6,7,8,9,10,ll-Hexahydro-1-Methoxy-5-Methyl-S,10-Methano-SE-Benzocyclononen-12-One, Oxime Using a procedure analogous tothat described in Example XIX, Method (B), for preparation of6,7,8,9,l0,11- hexahydro3-methoxy-5-methyl-5,IO-methano-SE-benzocyclononen-lZ-one, oxime thereis obtained from 21.5 g. of 6,7,8,9,10,11 hexahydro-l-methoxy 5methyl-5,10- methano-5-benzoyclononen-12-one, 10.9 g. of the titleproduct, mp. 154-160" C.

I.R. analysis: 3.1-3.2, 6.0 1.

EXAMPLE XXV 5-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10'-Methano-Sg-BenzOcyclononen-12-One, Oxime EXAMPLE XXVI To prepared:6,7,8,9,10,11-hexahydro 5 benzyl-5,10- methano-SE-benzoyclononen-12-one,oxime treat 6,7,8,9, 10,11hexahydro-S-benzyl-S,10-methano-5g-benzocycloclononen-lZ-one withhydroxylamine hydrochloride as taught in Example XIX, Method (C).

To prepare: S-benzyl 6,7,8,9,10,11 hexahydro-3-methoxy5,10-methano-SE-benzocyclononen-12-one, oxime treat5-benzyl-6,7,8,9,10,1l-hexahydro 3 methoxy-5,10-methano-SEbenzocyclononen-12-one with hydroxylamine hydrochloride astaught in Example XIX, Method (C).

EXAMPLE XXVII 6,7,8,9,10,11-Hexahydro-3-Methoxy-5-Methyl-5,10-MethanO-SI I-Benzocyclononen-12-Amine (A) 6,7,8,9,10,11-Hexahydr0 3methOXy-S-methyI- 5,10-methano-SIT-benzocyclononen-12-one, oxirne (15 g.

0.058 m.), Raney nickel (3 tsps.), ethanol (100 m1.) and concentratedammonium hydroxide (50 ml.) are shaken with hydrogen at 45 p.s.i. and 45C. The catalyst is removed by filtration and the filtrate concentratedto remove solvent. The residue is distilled under reduced pressure toafford the title product (11 g.), b.p. l40-142 C. (0.2 mm.), HCl salt,m.p. 298-299 C.

Analysis. Calculated for C H ClNO: C, 68.21; H, 8.58; N, 4.96. Found: C,67.96; H, 8.63; N, 4.92.

(B) Undistilled 6,7,8,9,10,11 hexahydro-3-methoxy-5-methyl-5,10-methano-SE-benzocyclononen-12-amine (3 l g.) in dry ether(200 ml.) is treated with dry hydrogen chloride in ether until thesolution is acidic. The precipitated salt is collected, washed withether and dried to afford a product (32 g.), m.p. 257-267 C.

This product is dissolved in water (1,000 ml.) and methanol (180 ml.).Addition of concentrated hydrochloric acid (2 ml.), concentration atatmospheric pressure to 500 ml., collection of the precipitate obtainedon cooling, followed by washing and drying gives a product (20.0 g.),m.p. 302305 C. On the basis of infrared and nuclear magnetic resonancespectra this product is assigned the structure6,7,8,9,10,11-hexahydro-3-methoxy-5a-methyl-5,10-methano-5g-benzocyclononen-12fl-amine, hydrochloride.

Concentration of the mother liquors obtained after isolation of theB-amine product gives a product (2 g.), m.p. 262-273 C. Furtherconcentration to about 65 ml. clarifying and chilling gives crystals(5.9 g.), mp. 231- 236 C. which are collected with the aid of additionalcold water (50 ml.). Recrystallization is accomplished by dissolving inacetone-methanol (2:1), concentrating to onehalf volume then making upto the original volume with acetone. Repetition of theconcentration-dilution process three additional times followed bychilling gives a prodnot (4.5 g.), m.p. 237-240 C.

Analysis.Calculated for C H ClNO: C, 68.21; H, 8.58; N, 4.96; Cl, 12.54.Found: C, 68.40; H, 8.72; N, 5.02; Cl, 12.04.

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure 6,7,8, 9,10,1l-hexahydro-3-methoxy 5amethyl-5,10-methano- SE-benzocyclononen-12a-amine, hydrochloride.

EXAMPLE XXVIII 6,7,8,9,10,1l-Hexahydro-2-Methoxy-5a-Methyl 510-Methano-SE-Benzocyclononen-IZB-Amine Using a procedure analogous tothat described in Example XXVII(A) for preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl 5,10methano-SH-benzocyclononen-lZ-amine, there is obtained from 5.0 g. of6,7, 8,9,10,11 hexahydro-2-methoxy-5-methyl-5,10-methano- 5 I:I-benzoycyclononen-12-one, oxime 2.8 g. of the title product as itshydrochloride, mp. 284-287 C.

Analysis.Calculated for C H NOClZ C, 68.21; H, 8.58; N, 4.96. Found: C,68.09; H, 8.85; N, 4.96.

EXAMPLE XXIX 6,7,8,9,l0,1l-Hexahydro-1-Methoxy-5ot-Methyl- 5,10-Methano-5 1jI -Benz0cyclononen-12,8-Amine Using a procedure analogousto that described in Example XXVII(A) for preparation of6,7,8,9,10,11hexahydro-3-methoxy-5-methyl 5,10methano-SE-benzocyclononen-lZ-amine there is obtained from 10.5 g. of6,7, 8,9,10,11 hexahydro-l-methoxy-S-methyl-S,IO-methano-SH-benzocyclononen-12-one, oxime 7.4 g. of the title product as thehydrochloride, mp. 308-309 C.

Analysis.-Calculated for C H NOCl: C, 68.21; H, 8.58; N, 4.96. Found: C,68.12; H, 8.60; N, 4.84.

EXAMPLE XXX a-Methy1-5,6,7,8,9,10,11,12-Octahydro-5,1 l-M'ethano-Benzocyclodecen-13 fi-Amine 5-Methyl-5,6,7,8,9,10,11,12-octahydro5,11-methano- SE-benzocyclodecen-13-one, oxime (2.5 g.), Raney nickel (2g.), ammonium hydroxide (4 ml.) and ethanol (50 ml.) are shaken withhydrogen at 45 p.s.i. After hydrogen uptake ceases (approximately 7pounds versus 14 pounds theory) the solution is removed from theapparatus, filtered, and concentrated. The residue (pink oil) iscombined with fresh Raney nickel, ammonium hydroxide, and ethanol andhydrogenated at 50 p.s.i. and 50- 60 C. When completed the solution isworked up as above. The residue, a colorless oil, is converted to thehydrochloride salt, filtered, washed, and dried. The salt isrecrystallized from water to give the title compound, as thehydrochloride, 1.15 g., m.p. 335 C.

Analysis.-Calculated for C H ClN: C, 17.29; H, 9.10; N, 5.27. Found: C,72.12; H, 9.45; N, 5.28.

EXAMPLE XXXI 6,7,8,9,10,1l-Hexahydro-5ot-Methyl-5,IO-Methano- 5 PI-Benzocyclononen-12/3-Amine 6,7,8,9,10,l1-Hexahydro 5 methyl 5,10methano- 5g benzocyclononen 12 one, oxime (2.5 g.), Raney nickelcatalyst (6 g.) in 25 ml. of concentrated ammonium hydroxide and 50 ml.of ethanol are shaken with hydrogen at 50 p.s.i. and 45 C. Afterhydrogen uptake stops the catalyst is filtered off, the filtrateconcentrated, and the residue converted to the hydrochloride salt (2.8g.); recrystallization from water gives the title product as itshydrochloride, m.p. 315 C.

Analysis.Calculated for C N ClN: C, 71.62; H, 8.81; N, 5.53. Found: C,71.62; H, 8.81; N, 5.86.

EXAMPLE XXXII 5Ethyl-6,7,8,9,10,1 l-HeXahydro-3-Methoxy-5,10-Methano-SH-Benzocyclononenl Z-Imine Using a procedure analogous to thatdescribed in Example XXVII(A) for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl 5,10 methano 5gbenzocyclononen 12 aminethere is obtained from 3.5 g. of 5-ethyl 6,7,8,9,10,11-hexahydro 3methoxy-5,10- methano-5g-benzocyclononen-l2-one, oxime 1.6 g. of thetitle product, b.p. l60 C. (0.5 mm.).

1.R. analysis: 6.1

Addition of ethereal hydrogen chloride to the title product in ethergives the hydrochloride salt, mp. 252-255 C. (dec.).

Analysis.-Calculated for C H NOCI: C, 69.48; H, 8.23; N, 4.77. Found: C,69.25; H, 8.28; H, 4.72.

EXAMPLE XXX III 5-Ethyl-6,7,8,9,10, 1 1-Hexahydro-3-Methoxy-5 ,10-Methano-SE-Benzocyclononen-12-Amine (A) Using a procedure analogous tothat described in Example XXVII(A) for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy 5 methyl 5,10 methano-5E- benzocyclononen-12-aminethere is obtained from 5-ethyl- 6,7,8,9,10,l1-hexahydro 3 methoxy5,10-methano- SE-benzocyclononen-l2-imine (4.0 g.) approximately 3.5 g.of title product which is converted to its solid hydrochloride salt,m.p. 226231 C.

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure 50:.- ethyl-6,7,8,9,10,ll-hexahydro 3methoxy-5,10-methano- 5I -benzocyclononen-12fi-amine, hydrochloride.

Analysis.Calculated for C H NOCl: C, 69.01; H, 8.86; N, 4.73. Found: C,68.76; H, 8.94; N, 4.72.

(B) Using a procedure analogous to that described in Example XXVII(A)for the preparation of 6,7,8,9,l0,11- hexahydro 3 methoxy 5methyl-5,10-methano-5H- benzocyclononen-12-amine, from 5-ethyl6,7,8,9,10,l 1- hexahydro 3methoxy-5,lO-methano-SE-benzocyclononen-12-one, oxime there is obtaineddistilled title product which is shown by gas chromatography-massspectra data to be approximately a 8 to 1 mixture of epimeric amines.Dissolving 70 g. of this mixture in 1100 ml. of dilute aqueoushydrochloric acid, filtering the solution through diatomaceous earth andallowing it to stand 1 day at room temperature and for 2 days at 10gives 64 g. of the hydrogen chloride, hydrate salt of Sat-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy 5,10-methano 5 Hbenzocyclononen-12fi-amine with m.p. 25 3-25 6.

Analysis-Calculated for C H NO-NCl-H O: C, 65.05; H, 8.99; N, 4.46.Found: C, 65.26; H, 9.01; N, 4.50.

(C) The filtrate recovered from (B) above is made basic with aqueoussodium hydroxide, extracted with ether and the ether extracts dried andconcentrated to an oil. This oil is chromatographed on 300 g. of silicagel. Elution with a solution of 3 parts benzene, 1 part chloroform gives3.0 g. of pure 5a-ethyl-6,7,8,9,10,11-hexahydro-3- methoxy5,10-methano-SIi-benzocyclononen-IZa-amine. Conversion of the amine toits hydrogen chloride salt in ether gives a crystalline salt with m.p.182185 Analysis.Calculated for C H NOC1: C, 69.01; H, 8.86; N, 4.73.Found: C, 68.73; H, 8.91; N, 4.75.

EXAMPLE XXXIV 5,6,7,8,9,10-Hexahydro-3-Methoxy-5-Methyl-5,9-

Methano-Benzocycloocten- 1 l-Amine (A) Using a procedure analogous tothat described in Example XXVII(A) for the preparation of 6,7,8,9,10,11-hexahydro 3 methoxy 5 methyl-5,10-methano-5 H benzocyclononen-lZ-aminethere is obtained from 5,6,7, 8,9,10-hexhydro 3 methoxy 5methyl-5,9-methano benzocycloocten-ll-one, oxime (4.2 g.), 2.7 g. of thetitle compound, b.p. 125-129 C. (0.1 mm.).

A sample is converted to the hydrochloride salt which crystallizes fromethanolzether, m.p. 262-264 C.

Analysis.--Calculated for C H ClNO: C, 67.27; H, 8.28; N, 5.23. Found:C, 67.16; H, 8.48; N, 5.14.

(B) Using a procedure analogous to that described in Example XXV:1I(A)for the preparation of 6,7,8,9,10,11- hexahydro 3 methoxy 5methyl-SJO-methanQ-SH- benzocyclononen-12-amine, from5,6,7,8,9,10-hexahydro- 3-methoxy 5 methyl 5,10-methano-5H-benzocyclooctene-ll-one, oxime, there is obtained distilled titleproduct which is shown by gas chromatography, mass spectral data to be a3 to 2 mixture of amino epimers. By repeated recrystallization ofhydrogen chloride salt of 27 g. of the epimeric amine mixture fromethanol-ether, there is obtained 16.3 g. of product, m.p. 270272, whichis assigned the structure 5,6,7,8,9,10-hexahydro-3-methoxy- Sec-methyl5,9-methano-benzocycloocten-1lot-amine, hydrochloride.

Analysis.-Calculated for C H NOCl: C, 67.27; H, 8.28; N, 5.23. Found: C,67.17; H, 8.48; N, 5.14.

(C) Concentration of the combined mother liquors from (B) gives aresidue which is crystallized from acetonitrile and then repetitivelyrecrystallized from ethanol ether to give a product, m.p. 300-302, whichis assigned the structure 5,6,7,8,9,10-hexahydro-3-methoxy-5u-methyl 5,9methano-benzocycloocten-1l/i-amine, hydrochloride.

Analysis.-Calculated for C H NOCl: C, 67.27; H, 8.28; N, 5.23. Found: C,67.14; H, 8.24; N, 5.24.

EXAMPLE XXXV 3-Methoxy-5u-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-13B-Amine Using a procedure analogous tothat described in Example XXX for the preparation of5-methyl-5,6,7,8,9,10, 11,12 octahydro 5,11 niethano benzocyclodecen-13-amine there is obtained from 3-methoxy-5-methyl-5,6,7,8,9,10,11,12-octahydro 5,11 methanobenzocyclodecem 13-one, oxime (18.5g), Raney nickel (3 tablespoons), 100 ml. ofethanol and 50 ml. ofconcentrated ammonium hydroxide; after distillation 11.1 g. [b.p. 140145C. (1.2 mm.)] of the title product which is converted to thehydrochloride salt which recrystallizes from water, m.p. 311-312 C.

Analysis.Calculated for C H CINO: C, 69.13; H, 8.86; N, 4.73. Found: C,69.17; H, 9.16; N, 4.70.

EXAMPLE xxxvr To prepare: 6,7,8,9,l0,11 hexahydro-5-benzyl-5,10 methano5g benzocyclononen-lZ-amine (hydrochloride salts, m.p. 154l58 C. reduce6,7,8,9,10,11-hexahydro- 5-benzyl-5,10-methano 5H benzocyclononen 12one, oxime as taught in Example XXVII.

To prepare: 5 benzyl-6,7,8,9,10,1l-hexahydro-3-methoxy-5,10-methanoSH-benzocyclononen-12-amine (hydrochloride salt, m.p. 152156 C.) reduce5benzyl-6,7, 8,9,10,11-hexahydro 3methoxy-5,IO-methano-SH-benzocyclononen-12-one, oxime as taught inExample XXVII.

EXAMPLE XXXVII 6,7, 8,9, 1 0, 1 1-Hexahydro-3-Methoxy-N,5 a-Dimethyl-5,10-Methano-SHBenzocyclononen-IZa-Amine 6,7,8,9,10,11-hexahydro 3methoxy-5a-methyl-5,10- methano-SH-benzocyclononen-12oc-amine,hydrochloride (2.5 g.), saturated aqueous sodium bicarbonate (50 ml.),methylene chloride (50 ml.) and. ethylchloroformate (3 ml.) are stirred,at room temperature, for 4 hours. The organic layer is separated, Washedsuccessively with aqueous sodium carbonate, hydrogen chloride and sodiumchloride, dried and concentrated to give 2.6 g. of oil. This oil isadded to a mixture of 1 g. of lithium aluminum hydride intetrahydrofuran and the resulting mixture is refluxed overnight. Two ml.of Water is added and the mixture is filtered. Concentration of thefiltrate gives 2.1 g. of oil which is converted to 1.8 g. of hydrogenchloride salt with m.p. 249-250 after recrystallization from ethanol-ether.

Analysis.Calculated for C H NOCl: C, 69.01; H, 8.86; N, 4.73. Found: C,68.53; H, 9.08; N, 5.13.

EXAMPLE XXXVIII 6,7,8,9,10,11-Hexahydro-3-Methoxy-N,N,Su-Trimethyl- 5 1O-Methanodg-Benzocyclononen- 1 Za-Amine In a manner analogous to thatdescribed in Example XXXVII for the preparation of6,7,8,9,10,11-hexahydro- 3-methoxy-N,5a dimethyl 5,10 methano-5Hbenzocy- ClOl'lOIlEIl-lZoc-flll'litle, from 1.2 g. of6,7,8,9,10,11-hexahydro 3methoxy-N,5o-dimethyl-5,IO-methano-SH-benzocyclononen-lh-amine there isobtained 0.90 g. of the hydrogen chloride salt of the title product withm.p. 200- 202.

Analyszs.-Calculated for C H NOCI: C, 69.76; H, 9.11; N, 4.52. Found: C,69.28; H, 9.12; N, 4.69.

EXAMPLE XXXIX 6,7,8,9,10,11-Hexahydro-3-Methoxy-N,N,5otTrimethy1-5,10-Methano Sfl-Benzocyclononen-l2,8-Amine In a manner analogous tothat described in Example XXXVII for the preparation of6,7,8,9,10,11-hexahydro- 3-methoxy-N,5 x dimethyl 5,10methano-SH-benzocyclononen-12a-amine, from 1.2 g. of6,7,8,9,10,11-hexahydro 3 methoxy-N,5a-dimethyl-5,10-methano-5 H-benzocyclononen-lZa-amine there is obtained 1.0 g. of the hydrogenchloride salt of the title product with m.p. 207- 209.

Analysis.Calculated for C H NOCl- AH O: C, 68.79; H, 9.14; N, 4.46.Found: C, 68.83; H, 9.36; N, 4.69.

EXAMPLE XL 5 a-Ethyl-6,7,8,9,10,1 1-Hexahydro-3-Methoxy-N-Methyl-5,10-Methano-SH-Benzocyclononen-12B-Arnine In a manner analogous to thatdescribed in Example XXXVII for the preparation of6,7,8,9,10,11-hexahydro- 3-methoxy-N,5a-dimethyl 5,10methano-SH-benzocyclononen-12a-amine, from 8.0 g. of5a-ethyl-6,7,8,9,10,11- hexahydro 3 methoxy 5,10 methano-Sg-bmzocyclmnonen-12fl-amine there is obtained 5.5 g. of the hydrogen chloride saltof the title product with m.p. 282-284 dec. on recrystallization fromethanol-ether.

AnaZysis.Calculated for C H NOCl: C, 69.76; H, 9.11; N, 4.52. Found: C,69.29; H, 9.22; N, 4.61.

23 EXAMPLE XLI 5 a-Ethyl-6,7,8,9, 10,11-Hexahydro-N,N-Dimethyl-3-Methoxy-5,10-MethanO-SE-Benzocyclononen-12,8-AlnineIn a manner analogous to that described in Example XXXVII for thepreparation of 6,7,8,9,l0,l1-hexahydro- 3-methoxy-N,5a-dimethyl 5,10methano-5g-benzocyclononen-12a-amine, from 4.0 g. of5a-ethyl-6,7,8,9,l0, ll-hexahydro 3 methoxy-N-methyl-S,IO-methano-SE-benzocyclononen-12,8-amine there is obtained 2.65 g. of the hydrogenchloride salt of the title product with m.p. 162-165 onrecrystallization from ethanol-ether.

Analysis.-Calculated for C H NOCl: C, 70.56; H, 9.34; N, 4.33. Found: C,70.14; H, 9.30; N, 4.30.

EXAMPLE XLII 3-Methoxy-N,5a-Dimetl1yl-5,6,7,8,9,10,1 1,12-Octahydro- 5,11-Methanobenzocyclodecen-1 313-Amine3-Methoxy-N,N,5ot-Trimethyl-5,6,7,8,'9',10,151,12-Octahydro-Methanobenzocyclodecen-1 3fi-Amine In a manner analogous to that described in Example XXXVIIfor the preparation of 6,7,8,9,1'0,1l-hexahydro-3-methoxy-N,5a-dimethy1-5,10 methano 5E benzocyclononen-12a-amine, from4.0 g. of 3-methoxy-N,5a-dimethyl 5,6,7,8,9,10,11,12octahydro-methanobenzocyclodecen-13fl-amine there is obtained 2.0 g. ofthe hydrogen chloride salt of the title product with m.p. 195198 onrecrystallization from ethanol-ether.

Analysis-Calculated for C H NOCl-H O: C, 66.74; H, 9.43; N, 4.10. Found:C, 66.61; H, 9.39; N, 3.96.

EXAMPLE XLIV 5,6,7,8,9,l-Hexahydro-3-Methoxy-N,5a-Dimethyl-5,9-Methanobenzocyc1ooctene-1 lp-Amine In a manner analogous to thatdescribed in Example XXXVII for the preparation of6,7,8,9,10,11-hexahydro- 3-methoxy-N,Sa-dimethyl-S,10 methano gbenzocyclononene-12a-amine, from 1.5 g. of5,6,7,8,9,10-hexahydro-3-methoxy 5 on methyl 5 ,9methanobenzocyclooctene-llB-amine there is obtained 1.2 g. of thehydrogen chloride salt of the title product with m.p. 266-267".

Analysis.--Calculated for C H NOCl: C, 68.19; H, 8.58; N, 4.97. Found:C, 67.88; H, 8.88; N, 4.80.

EXAMPLE XLV 5 a-Ethyl-6,7, 8 ,9, 10,1 1-Hexahydr0-3 -Meth0xy-N-Methyl-5,10-Methano-SE-Benzocyclononen-12fi-Amine In a manner analogous to thatdescribed in Example XXXIX for the preparation of6,7,8,9,10,11-hexahydro- 3-methoxy-N,5et-dimethyl-5,10 methano 5Ebenzocyclononen-lZfi-amine, from 1.2 g. of 5u-ethyl-6,7,8,9,10,11hexahydro 3 methoxy 5,10 methano-Sg-benzocydononen-lZfl-amine there isobtained 0.90 g. of the hydrogen chloride salt of the title product withm.p. 284-285 dec. on recrystallization from ethanol-ether.

Analysis.-Calcu1ated for C H NOCl- AH O: C, 68.77; H, 9.14; N, 4.46.Found C, 69.69; H, 9.19; N, 4.42.

24 EXAMPLE XLVI N-Allyl-6,7,8,9,1'0,1l-Hexahydro 3 MGthOXY-Soc-Methyl-5,10-Methano 5E Benzocyclononen-lZB- Amine6,7,8,9,10,11-Hexahydro 3 methoxy-5u-methyl-5,10methano-SE-benzocyclononen-12,8-amine (1.7 g.), allylbromide (0.85 g.),diisopropyl ethyl amine (1.3 g.) and benzene (10 ml.) are heated atreflux for 3 hours. The mixture is cooled, diluted with ether andfiltered. The solvents are removed under reduced pressure and theresidue distilled to give the title product (1.3 g.), b.p. 144-146 C.(0.2 mm.). The distilled product is taken up in ether and treated with aslight excess of hydrogen chloride in ether to give the hydrochlorideaddition salt of the title product (1.3 g.), m.p. 200-202" C.

Analysis.Calculated for C1QH28C1NO: C, 70.95; H, 8.74; N, 4.35. Found:C, 70.50; H, 8.77; N, 4.46.

EXAMPLE XLVII N-Allyl-5,6,7,8,9,10 Hexadhydro 3 Methoxy-5u-Methyl-5,9-Methanobenzocyclooctene-1 lot-Amine Using a procedureanalogous to that described in Example XXXVI for the preparation ofN-allyl-6,7,8,9,l0,11- hexahydro 3 methoxy 5amethyl-5,10-methano-5gbenzocyclononen 12B amine there is obtained from5,6,7,8,9,10-hexahydro 3methoxy-5u-methyl-5,9-methano-benzocycloocten-ll-amine (1.4 g.), 1.3 g.of the title product, b.p. 148153 C. (0.3 mm.). A sample is converted tothe hydrochloride.

Analysis.--Calcl1lated for C H ClNO: C, 70.22; H, 8.51; N, 4.55. Found:C, 69.75; H, 8.73; N, 4.47.

EXAMPLE XLVIII 6,7,8,9,1'0,1l-Hexahydro 3 Methoxy-M-Methyl-N-Phenethyl-5,10-Methano 5 I 1 Benzocyclononen- 12fl-Amine A mixture of6,7,8,9,10,11-hexahydro 3methoxy-5amethyl-S,10-methano-SE-benzocyclonone-12/3-amine (2.4 g.),phenethyl bromide (3 g.), and diisopropyl ethylamine (1.3 g.) in xylene(20 ml.) is heated at reflux for 18 hours. After cooling ether is addedml.) and the solid material is filtered otf and washed with ether. Thecombined filtrate is extracted with dilute hydrochloric acid. The solidresidue is dissolved in warm water, and added to the acid extract. Thesolution is basified with 10% sodium hydroxide and the oily layer whichseparates is taken into ether. After removal of solvent the residue isdistilled and the fraction boiling at 198/.2 mm. is collected. This isconverted to the hydrochloride salt in ether which is recrystallizedfrom i-propanol to give the title product as its hydrochloride salt,m.p. 243-245 C.

Analysis.-Calculated for C H ClNO: C, 75.80; H, 8.36; N, 3.63. Found: C,74.55; H, 8.74; N, 3.55.

EXAMPLE XLIX 6,7,8,9,l0,l1-Hexahydro 3 Methoxy-5a-Methyl-N- (3-Methyl 2Butenyl)-5,l0-Methano-5-Benzocyc1ononen-12p-Amine6,7,8,9,10,11-Hexahydro 3 methoxy-5-methyl-5,10-methano-SE-benzocyclononen-12-amine (4.5 g.), 3,3-dimethylallylbromide(4.5 g.), diisopropyl ethylamine (5.75 g.) and xylene (60 ml.) areheated at reflux for 4 hours. The mixture is cooled, diluted with etherand filtered. The solvent is removed under vacuum and the residue isdistilled to give the title product (1.2 g.), b.p. l66-170 C. (0.2 mm.).A sample is converted to the hydrochloride and recrystallized fromethanol, m.p. 295-298 C.

Analysis.Calculated for C H CINO: C, 69.01; H, 8.86; N, 4.73. Found: C,68.90; H, 8.92; N, 4.83.

25 EXAMPLE L 5,6,7,8,9,10 hexahydro 3 methoxy 5a-rnethyl-5,9-methanobenzocycloocten-llot-amine (1.4 g.) diisopropylethylamine (1.3g.), and 1-chloro-3-methyl-2-butene (0.7 g.) are refluxed 7 hours inxylene. The reaction is cooled to room temperature, filtered and thefiltrate extracted with 2N hydrochloric acid. The aqueous extract isbasified and extracted with ether. The ether extract is then washed withwater, dried over sodium sulfate, concentrated in vacuo, and the residuedistilled under reduced pressure to give the title product (1.5 g.),b.p. 150155 C. (0.5 mm.) Treatment of the product in ether with hydrogenchloride gives the hydrochloride, m.p. 166-169 C.

Analysis.-Calculated for C H CINO: C, 71.51; H, 9.00; N, 4.17. Found: C,71.58; H, 9.09; N, 4.20.

EXAMPLE LI 12B-Amin0-6,7,8,9,10,1l-Hexahydro-5a-Methyl-5,l0-Methano-5E-Benzocyc1ononen-3-Ol A solution of 6,7,8,9,10,11hexahydro-3-methoxy-5amethyl 5,10 methano-5g-benzocyclononen-12fi-amine(1.19 g.) in 48% hydrobromic acid (15 ml.) is refluxed 30 minutes undernitrogen. The mixture is cooled, diluted with water (50 m1.), filteredand evaporated to dryness under reduced pressure. The residue isdissolved in ethanol (50 ml.) and again taken to dryness. Redissolvingin ethanol (25 ml.) addition of ether (50 ml.) and stand ing in the coldgives crystals which are recrystallized from i-propanol to give thehydrobromide salt of the title product as the i-propanolate (0.72 g.),m.p. 246248 C.

Analysis.-Calculated for C H BrNO C, 58.10; H, 8.07; N, 3.76. Found: C,57.52; H, 8.71; N, 3.69.

EXAMPLE LII 12B-Amino-6,7,8,9,10,1l-Hexahydro-Sa-Methyl-S,10-Methano-Sg-Benzocyclononen-Z-Ol Using a procedure analogous to thatdescribed in Example LI for the preparation of 12/3-amino-6,7,8,9,10,11hexahydro 5a methyl 5,10-methano-5E-benzocyclononen-3-ol there isobtained from approximately 1.2 g. of 6,7,8,9,10,1l hexahydro 2 methoxy5-methyl-5,10- methano-SE-benzocyclononem12-amine, 1.2 g. of thehydrogen bromide salt of the title product, m.p. 299- 303 C.

AnaIysis.--Calculated for C H BrNO: C, 57.69; H, 7.10; N, 4.49. Found:C, 57.53; H, 7.13; N, 4.44.

EXAMPLE LIII 13,6-Amin-5a-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-3-Ol 3 methoxy ozmethyl5,6,7,8,9,10,11,12-octahydro- 5,11 methanobenzocyclodecen-1B/R-amine (3 g.) is refluxed in 60 ml. 48% aqueoushydrobromic acid for one hour. The mixture is poured into ice (100 g.)and stirred. The precipitate is then filtered off, washed with coldwater, then with ether and dried. Recrystallization from water (aftertreating with activated charcoal) gives the title product, 1.85 g., m.p.269270 C.

Analysis.-Calculated for C H BrNO- /2H O: C, 57.18; H, 7.52; N, 3.97.Found: C, 57.22; H, 7.61; N, 414.

EXAMPLE LIV 12fi-Amino-6,7,8,9,10,1l-Hexahydro-5wMethyl-5,10Methano-SH-Benzocyclononenl-Ol Using a procedure analogous to thatdescribed in Example LI for the preparation of 12/3-amino-6,7,8,9,10,1lhexahydro 50c methyl 5,10-methano-5-benzocyclon0nen-3-ol, there isobtained from approximately 1.6 g. of 6,7,8,9,10,11 hexahydrol-rnethoxy-5-methyl-5,10-

methano-SE-benzocyclononen-12-an1ine, 1.75 g. of the hydrogen bromide.salt of the title product, m.p. 245- 250 C.

Analysis.-Calculated for C H BrNO: C, 57.69; H, 7.10; N, 4.49. Found: C,57.40; H, 7.02; N, 4.47.

EXAMPLE LV 12fi-Amino-6,7,8,9,10,11-Hexahydro-5a-Ethyl-5,10- Methano-5I-Benzocyclononen-3-01 A mixture of 50: ethyl 6,7,8,9,10,11-hexahydro-5,10- methano-3-methoxy-5 H -benzocyclononen-1Zfl-amine (2.0 g.) andml. of 48% hydrobrornic acid is refluxed for one-half hour, thenconcentrated to a viscous oil. The oil is dissolved in water and treatedwith concentrated aqueous ammonia. Filtration gives 1.7 g. of a crudeproduct, m.p. 191 C. Recrystallization from ethyl acetate gives thetitle product, m.p. 201-204 C.

Analysis.Calculated for C H NO: C, 78.32; H, 9.45; N, 5.71. Found: C,77.93; H', 9.68; N, 5.88.

EXAMPLE LVI 1lu-(Dimethylamino)-5,6,7,8,9,IO-HeXahydro-Su-Methyl-5,9-Methano-B enzocycloocten-3-Ol 5,6,7,8,9,10hexahydro-3-methoxy-N,N,5a-trimethyl- 5,9methano-benzocycloocten-lla-amine (1.2 g.) is refiuxed for one hourunder a dry nitrogen atmosphere in 13 ml. of aqueous 48% hydrobrornicacid. Concentration of the solution affords a residue which oncrystallization from ethanol-ether gives the title product as itshydrobrornic acid salt, m.p. 268-271 C.

Analysis.-Calculated for C I-I NOBr: C, 58.89; N, 7.41; H, 4.29. Found:C, 58.80; N, 7.52; H, 4.22.

EXAMPLE LVII 11 u-Amino-5,6,7,8,9,10-Hexahydro-5a-Methyl-5,9-Methanobenzocycloocten-3-01 In a manner analogous to that described inExample LI for the preparation of 12fi-amino-6,7,8,9,10,11-hexahydro5ot-methyl5,10-methano-SE-benzocyclononen-3-ol, from 2.0 g. of5,6,7,8,9,10 hexahydro 3methoxy-5amethyl-5,9-methanobenzocyclooctene-1lwamine there is obtained2.3 g. of the hydrogen bromide, ethanolate salt of the title productwith m.p. 277-280 on recrystallization from ethanol-ether.

Analysis.-Calculated for C H NOBr- /2C H OH: C, 56.07; H, 7.22; N, 4.36.Found: C, 55.86; H, 7.37; N, 4.10.

EXAMPLE LVIII 1 l ,li-Amino5,6,7,8,9,10=Hexahydro-5a-Methyl-5,9-Methanobenzocycloocten-3 -01 In a manner analogous to that described inExample LI for the preparation of 12B-amino-6,7,8,9,10,1l-hexahydro 5amethyl 5,10 methane 5g benzcocyclononen-3-ol, from 1.25 g. of5,6,7,.8,9,10-hexahydro-3-methoxy 50c methyl 5,9 methanobenzocyclooctene11/3- amine there is obtained 1.05 g. oi the hydrogen bromide salt ofthe title product with m.p. 305-310 dec. on recrystallization fromethanol-ether.

Analysis.--Calculated for C H NOBr: C, 56.38; H, 6.76; N, 4.70. Found:C, 56.01; H, 6.79; N, 4.63.

EXAMPLE LIX 12a-Amino-6,7,8,9,10,11-Hexahydro-5a-Methyl-5,10-Methano-Sfi-benzocyclononen-3-Ol In a manner analogous to that describedin Example LI for the preparation of 12/i-amino-6,7,8,9,10,1l-hexahydro-Sa-methyl-S,10-methano-SE-benzocyclononen-Fr-ol, from 1.2 g. of6,7,8,9,10,11-hexahydro-3-methoxy-5u-methyl-5,10-methano-SE-benzocyclononen-IZa-amine there is obtained 1.1 g. ofthe hydrogen bromide salt of the title compound with m.p. 130345 onrecrystallization from acetonitrile.

Analysis.Calculated for C H NO-HBr-%CH CN: C, 57.72; H, 7.11; N, 5.43.Found: C, 57.47; H, 7.00; N, 5.57.

EXAMPLE LX 12a-Amino-6,7,8,9,10,1l-Hexahydro-Sa-Ethyl-S,10-Methano-SE-Benzocyclononen-3-Ol In a manner analogous to that describedin Example LI for the preparation of 12fi-amino-6,7,8,9,l0,1l-hexahydro5a methyl 5,10 methano 5g benzocyclononen-3-ol, from 1.0 g. of5-a-ethyl-6,7,8,9,l0,ll-hexahydro 3 methoxy 5,10 methano 5gbenzocyclononen- 12a-amine, there is obtained 0.72 g. of the hydrogenbromide salt of the title product with m.p. 266270 on recrystallizationfrom ethanol-ether.

Analysis.Calculated for C H NOBr: C, 58.89; H, 7.41; N, 4.29. Found: C,58.50; H, 7.47; N, 4.10.

EXAMPLE LXI 6,7,8,9,l0,11-Hexahydro-3-Methoxy-N,5a-Dimethyl-5,10-Methano-SH-Benzocyclononen- IZB-Amine 6,7,8,9,10,11 Hexahydro 3 methoxy5 methyl- 5,10-methano-SH-benzocyclononen-12-one (3 g.), calcium oxide(2 g.), and liquid methyl amine (1O ml.) are heated in a sealed vesselat 180-190 C. for 18 hours. After cooling the mixture is diluted withether and filtered to separate the hydrated calcium oxide. The filtrateis concentrated to an oil which is taken up in ethanol and shaken withhydrogen at 45 p.s.i. in the presence of platinum dioxide catalyst. Thecatalyst is removed by filtration, rinsed thoroughly with ethanol andcombined filtrate is concentrated in vacuo. The residue was distilledunder reduced pressure to give the title product (1.8 g.), b.p. 138-144C. (0.2 mm.). For analytical purposes a sam ple is converted to thehydrochloride which crystallizes from ethanol, m.p. 295298 C.

Analysis.Calculated for C H CINO: C, 69.01; H, 8.86; N, 4.73. Found: C,68.90; H, 8.92; N, 4.83.

EXAMPLE LXII 5 ,6,7,8,9, -Hexahydro-3 -Methoxy-5aMethyl-N-Phenethyl-5,9-Methanol-Benzocycloocten-1 1 a-Amine Using aprocedure analogous to that described in Example LXI for the preparationof N,5a-dimethyl-6,7,8,9, 10,11 hexahydro 3 methoxy 5,10 methano 5H-benzocyclononen-lZfi-amine there is obtained from 5,6,7, 8,9,10hexahydro 3 methoxy 5 methyl-5,9 methanobenzocycloocten-ll-one (2.3 g.)1.80 g. of the title product, b.p. 170-200 C. (0.5 mm.). A sample isconverted to the hydrochloride salt.

Analysis.-Calculated for C H CINO: C, 74.27; H, 8.12; N, 3.77. Found: C,74.23; H, 8.29; N, 3.59.

EXAMPLE LXIII 5,6,7,8,9,10-Hexahydro-3-Methoxy-N,5a-Dimethyl-5,9-Methano-Benzocycloocten-1lot-Amine Using a procedure analogous to thatdescribed in Example LXI for the preparation of 6,7,8,9,10,11-hexahydro-3 methoxy N,5oc dimethyl-5,10 methano 5 I- I benzocyclononen-lZfi-aminethere is obtained from 5,6,7,8, 9,l0-hexahydro-3-methoxy-5-methyl 5,9methano-benzocycloocten-ll-one (9.5 g.), 5.4 g. of the title product asthe hydrochloride salt, m.p. 232-236 C.

Analysis.Calculated for C H ClNO: C, 68.19; H, 8.58; N, 4.97. Found: C,67.83; H, 8.45; N, 4.91.

EXAMPLE LXIV N-Allyl-N,5a-Dimethyl-5,6,7,8,9,10-Hexahydro-3-Methoxy-5,9-Methano-Benzocycloocten-1lot-Amine N allyl 5,6,7,8,9,10hexahydro 3 methoxy 50cmethyl-5,9-methano-benzocycloocten-1lot-amine (3g.),

ethylchloroformate (3 ml.), saturated aqueous bicarbonate (50 ml.) andmethylene chloride (25 ml. are stirred vigorously overnight at roomtemperature. The layers are then separated, the methylene chloridewashed with 2N hydrochloric acid, dried over potassium carbonate andconcentrated in vacuo. The residue obtained (3.3 g.) is dissolved intetrahydrofuran ml.), stirred and refluxed under nitrogen with lithiumaluminum hydride (1 g.) for 20 hours. The mixture is cooled, water (1.5ml.) added to destroy excess hydride, and aluminum salts removed by filtration. The filtrate is dried and concentrated in vacuo and the residuedistilled to give the title product (1.4), b.p. C. (0.5 mm.). A portionis dissolved in ether, treated with hydrogen chloride, the crystalsrecovered by filtration and recrystallized from ethyl acetate to give ahydrochloride salt, m.p. 164166 C.

Analysis.Calculated for C H ClNO: C, 70.89; H, 8.77; N, 4.35. Found: C,71.06; H, 9.07; N, 4.53.

EXAMPLE LXV 5,6,7,8,9,10-Hexahydro-3-Methoxy-N,N,5-Trimethyl-5,9-

Methano-Benzocycloocten-1 l-Amine Using a procedure analogous to thatdescribed in Example LXIV for the preparation ofN-allyl-N,5-dimethyl-5,6, 7,8,9,10 hexahydro 3 methoxy 5,9methanol-benzecycloocten-l l-amine there is obtained from N,5-dimethyl-5,6,7,8,9,10 hexahydro 3 methoxy 5,9 methanobenzocycloocten-ll-amine(11.1 g.), 8.1 g. of the title product, b.p. 125-230 C. (0.3 mm.). Theproduct in solution in ether is converted by treatment with hydrogenchloride to a crystalline hydrochloride salt. Recrystallization fromethano-ether gives a product (A), m.p. 190 which is recrystallized fromethanol-ether to give a prodnot having needle-shaped crystals, m.p.225-226 C.

Analysis.-Calculated for C H ClNO: C, 69.01; H, 8.86; N, 4.74. Found: C,68.89; H, 8.92; N, 4.70.

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure 5,6,7, 8,9,10 hexahydro-3-methoxyN,N,5u trimethyl 5,9- methano-benzocyclooctane-1lfl-amine,hydrochloride.

From the mother liquors remaining after crystallization of product (A),after concentration, is obtained a second product, m.p. 218223 C.,recrystallization from ethanol-ether gives a product having hexagonalcrystals, m.p. 221223 C.

Analysis.Calculated for: C H ClNO: C, 69.01; H, 8.86; N, 4.74. Found: C,68.89; H, 8.64; N, 4.74.

On the basis of infrared and nuclear magnetic reso nance spectra thisproduct is assigned the structure 5,6,7, 8,9,10-hexahydro-3-methoxyN,N,5oc trimethyl 5,9- methano-benzocyclooctane-1lot-amine,hydrochloride.

EXAMPLE LXVI N,5a-Dimethyl-N-Phenethyl 5,6,7,8,9,10 Hexahydro-3-Met-hoxy-S ,9-Methano-Benzocycloocten-1 lwAmine Using a procedureanalogous to that described in Example LX-IV for the preparation ofN-allyl-N,5-dimethyl- 5,6,7,8,9,10-hexahydro-3-methoxy 5,9methano-benzecycloocten-ll-amine there is obtained from 5,6,7,8,9,10hexahydro-3-methoxy-S-methyl-N-phenethyl 5,9methano-benzocycloocten-ll-amine (3.8 g.) 3.1 g. of the title product,b.p. -190 C. (0.3 mm.). Treatment of a portion of the product in acetonewith one equivalent of fumaric acid gives the fumarate salt which isrecrystallized from acetone as a hydrate, m.p. 149151 C.

Analysis. Calculated for C H NO A1H O: C, 71.53; H, 7.61; N, 2.98.Found: C, 71.58; H, 7.73; N, 2.98.

EXAMPLE LXVII N,5a-Dimethyl 5,6,7,8,9,10 Hexahydro-3-Methoxy-N-(3-Methyl-2-Butenyl)-5,9-Methano Benzocycloocten- Ila-Amine Using aprocedure analogous to that described in Example LXIV for thepreparation of N-allyl-N,5-dimethyl- 29 5,6,7,8,9,10-hexahydro-3-methoxy5,9 methanobenzocycloocten-ll-amine, there is obtained from5,6,7,8,9,10- hexahydro-3-methoxy-5-methyl-N-(3 methyl-2-butenyl)-5,9-methano-benzocycloocten1l-amine (3.6 g.) 2.6 g. of the titleproduct, b.p. ISO-155 C. (0.4 mm.). Treatment of a portion of theproduct in acetone with fumaric acid gives the crystalline fumaric acidsalt as a hydrate, m.p. 136-138 C.

Analysis-Calculated for: C H NO AH O: C, 69.19; H, 8.24; N, 3.22. Found:C, 69.20; H, 8.11; N, 3.32.

EXAMPLE LXVIII N,5u-Dimethyl-6,7,8,9,10,1l-Hexahydro 3 Methoxy-N-(3-Methyl-2-Butenyl)-5,10-Methano 521 Benzocyclononen-12fl-Arnine6,7,8,9,10,1l-Hexahydro-3-methoxy-5-methyl N (3-methyl-2-butenyl)-5,10-methano 5E benzocyclononen- 12-amine (3.5 g.),ethyl chloroformate (6 g.), saturated aqueous sodium bicarbonate (100ml.) and methylenedichloride (50 ml.) are stirred vigorously at roomtemperature for 24 hours. The layers are then separated and the organiclayer is washed with 2N hydrochloric acid, dried over potassiumcarbonate and concentrated in vacuo. The residue (3 g.) is dissolved intetrahydrofuran (50 ml.) and added to a suspension of lithium aluminumhydride in tetrahydrofuran (50 ml.) stirred and heated to reflux for 18hours. After cooling, water (4.5 ml.) is added and the reaction mixtureis stirred 30 minutes and filtered. The filtrate is dried over anhydroussodium sulfate and concentrated. The residue (2 g.) is treated withfumaric acid in acetone to give the fumarate salt of the title productas the hemihydrate (1.8 g.), m.p. 108-110 C.

Analysis. Calculated for C H NO /2H O: C, 69.02; H, 8.47; N, 3.08.Found: C, 68.82; H, 8.54; N, 2.94.

EXAMPLE LHX 12fi-Amino-6,7,8,9,10,11-Hexahydro-5wMethyl-5,10- Methano-5I:I -Benzocyclononen-3-Ol, Acetate (A) A mixture of12-amino-6,7,8,9,10,1l-hexahydro-S-methyl-5,10-methano-SE-benzocyclononen-3-ol (15.0 g), carbobenzyloxychloride (11.6 g.) and 100 ml. of saturated aqueous sodium bicarbonateare stirred for 30 minutes. Methylene chloride (100 ml.) is added andthe mixture stirred for 1 hour. The organic layer is separated, driedand concentrated. The residue is triturated with ethyl acetate andpentane, then filtered to give 24 g. of crude product. Recrystallizationfrom ethylacetatecyclohexane gives 18.3 g. of carbobenzyloxylated aminewith m.p. 103-110.

(B) A solution of the carbobenzyloxylated amine (5.0 g.) of part (A)above, acetic anhydride (10 ml.) and pyridine (50 ml.) is allowed tostand overnight. The solution is diluted with water and extracted withether. The ether extracts are Washed with 2% aqueous hydrochloric acid,dried and concentrated to give 5.1 g. of o-acetylated product shown tobe pure by thin layer chromatography.

(C) A solution of the o-acetyl product of part (B) above (2.5 g.) andhydrogen chloride gas (0.75 g.) in tetrahydrofuran (50 ml.) ishydrogenated in a Parr apparatus over 250 mg. of 10% palladium on carbonunder 40 lbs. of hydrogen pressure for 90 minutes. The catalyst isfiltered and concentration of the filtrate gives 2.2 g. of title productas a viscous glass. Crystallization of the glassy product fromtetrahydrofuran-ether gives crystalline12fi-amino-6,7,8,9,10,11-heXahydro-5a-methyl 5,10-methano-5flbenzocyclononen 3 ol, acetate, hydrochloride with m.p. 268dec.

Analysis.Calculated for: C H NO Cl: C, 65.90; H, 7.81; N, 4.52. Found:C, 65.38; H, 7.82; N, 4.48.

30 EXAMPLE LXX 12fi-Amino-6,7,8,9,10,11-Hexahydro 5a Methyl 5,10-Methano-SH-Benzocyclononen-3-ol, Cyclopropane Carboxylate (A) A solutionof 2.0 g. of the carbobenzyloxylated amine, described in Example LXIX,part (A), and 2.0 ml. of 'cyclopropane carboxoyl chloride in 10 ml. ofpyridine is allowed to stand overnight. The solution is diluted withWater and extracted with ether. The ether extracts are washed with 2%aqueous hydrochloric acid, dried and concentrated to an oil. The oil ischromatographed on 70 g. of activity III Woelm alumina. Elution withether gives 1.5 g. of oil Which is crystallized from ethyl acetatehexane to give 1.2 g. of O-cyclopropane carboxylate derivative with m.p.l04-109.

(B) In a manner analogous to that described in Example LXIX, part (C),for the preparation of 12-amino- 6,7,8,9,10,11 hexahydro5-methyl-5,10-methano-5 I I benzocyclononen-3-ol, acetate, from 1.0 g.of the O-cyclopropane carboxylate derivative of part (A) of above thereis obtained 0.45 g. of the hydrogen chloride salt of the title productwith m.p. 255-57 dec. on crystallization from tetrahydrofuran-ether.

Analysis. Calculated for C H NO Cl AH oz C, 67.04; H, 7.85; N, 4.12.Found: C, 66.79; H, 7.68; N, 4.14.

Example LXXI Resolution of5ot-Ethyl-6,7,8,9,10,11-HeXahydro-3-Methoxy-S,10-Methano-SE-Benzocyclononen-12,8-AmineA solution of5a-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-Sg-benzocyclononen-12,6-amine(64.6 g., 0.249 mole) in 300 ml. of methanol is added to a solution of41.5 g. (0.275 mole) of l-tartaric acid in 1400 ml. of methanol. Theresulting solution is warmed, filtered and diluted to 2000 ml. andallowed to stand for 3 days. Filtration then gives 36.1 g. of salt withm.p. 200-203 dec. and [a] =-27 (1% in dimethyl formamide).Recrystallization of the salt from methanol gives 29.1 g. with m.p.212-214 and [a] =32.3. This salt is converted to the free base bytreating it with aqueous sodium hydroxide extracting the aqueous mixturewith ether and drying the ether extracts over anhydrous magnesiumsulfate. On removal of the drying agent and the ether solvent 17.6 g. ofresolved base is obtained. This is converted to its hydrogen chloride,hydrate salt which has a m.p. 115-119 dec. and [a] =-44.1 (2% inmethanol).

To obtain the opposite rotating isomer, the mother liquors from thefirst crystallizations of above are concentrated, the residue treatedwith aqueous sodium hydroxide and extracted with ether. On drying theether extracts over anhydrous magnesium sulfate and concentrating theextracts, 41.5 g. of base is obtained. This is dissolved in 500 ml. ofmethanol and the solution is added to a solution of 26.4 g. ofd-tartaric acid in ml. of methanol. This solution is diluted to 1600 ml.and allowed to stand for 5 days. Filtration gives 36.7 g. of salt withm.p. 205-209 dec. and. [a] '=+30.3 (1% in dimethylformamide).Recrystallization of this salt from methanol gives 30.0 g. of salt withm.p. 209-211 dec. and [a] =|31.9. Conversion of this salt to free baseby the same procedure as for the minus rotating isomer described abovegives 16.8 g. of base. This is converted to its hydrogen chloridehydrate salt which has m.p. -119 dec. and [a] =-+44.5 (2% in methanol).

Example LXXII I Preparation of Plus and Minus Rotating Isomers of Amino6,7,8,9,10,1l-Hexahydro-M-Ethyl-S,lO-Methano-5I 1 -Benzocyclononen-3-o1(A) A mixture of optically pure minus rotating 50tethyl6,7,8,9,10,11-hexahydro-3-methoxy-5,IO-methano-Sg-benzoayclononen-lZfi-amine (9.5 g.) and 80 ml. of 48% aqueoushydrobromic acid are heated at the reflux temperature under a 'drynitrogen atmosphere for 30 minutes. The resulting solution isconcentrated to 40 ml., diluted to 150 ml. with water and basified withconcentrated aqueous ammonia. After allowing to stand one hour, themixture is filtered to give 89 g. of product with m.p. 185-191.Recrystallization of the product from ethyl acetate gives 7.5 g. withm.p. 194196 and [a] =-51.3 (2% in methanol).

(B) When optically pure plus rotating 5u-ethyl-6,7,8, 9,10,11hexahydro-3-methoxy-5,IO-methano-Sg-benzocyclononen-IZB-amine (9.3 g.)is treated with aqueous 48% hydrobromic acid as in (A), there isobtained 9.3 g. of crude product with m.p. 178l90. Recrystallization ofthis from ethyl acetate gives 7.0 g. of product with m.p. 194196 and [a]='|52.O (2% in methanol).

Example LXXIII When the following compounds are administered to rats bythe routes indicated, for evaluation of analgesic potential by theprocedure described hereinabove, they exhibit the effective dose-50values tabulated.

Effective dosaSO Mode of (mg/kg. Compound administration body wt.)

6,7,8,9,10,11-hexahydro-3-methoxy-fia- Intraperi- 25methyl-5,10-methano-5fl-benz0eyclotoneal. nonen-12fiamine. Oral 30 123-amino-6,7,8,0,10,1l-hexahydro-5a- Intraperi- 7. 5

methyl-5,10-methano-5g-benzoeyolotoneal. nonen-3-ol. Intramuscular 1. 8Oral 23 5a-ethyl-S,7,8,9,10,11-hexahydr0-3- Intraperi- 3. 5

methoxy5,ltl-methano-fig-benzotoneal. cyelonnen-12B-amine. Intramuscular13. Oral 11 1QB-amino-fi,7,8,0,10,11-hexahydro'5alngraperli- 3. 5

onea ethyl-5,10-meth ano-Sfi-benzocyclo- Intramus- 0. 25 n0nen'3-0l.cular.

Oral 12 3-methoxy-5a-methy1-5,6,7,8,9,10,11,12- Intraperi- 4. 5

octahydr0-5,11-methan0-benzoeyclo toneal. decen-BB-amine. Intramus- 15 cular. Oral 9 13/3-amino-5a-rnethyl-5,6,7,8,9,10,11.12- Intraperi- 1. 1

octahydro-5.ll-methano-benzocyclotoneal. decen ii-ol. Intramus- 0. 47

cular. Oral 9 )-13B-amino-5,6,7,8,9,10,11,12oetahy- Intraperi- 0. 78

dro-Bwmethyl-S,ll-methano-benzotoneal. cyclodecen-irol. lntramus- 0. 09

cular. Oral 2. 0

EXAMPLE LXXIV 1-Ethoxycarbonyl-2-Indanone To a stirred mixture of sodiumhydride (126 g. of a 57% suspension in Nujol), 2000 ml. of benzene and 2m1. of ethanol heated at its reflux temperature under dry nitrogen isadded dropwise the diethyl ester of o-phenylene-diacetic acid (335.6 g.)in 700 ml. of benzene. The mixture is refluxed 1.5 hours, poured intowater and extracted with ether. The ether extracts are dried andconcentrated to give an oil which is crystallized from ethanol-water togive 220 g. of title product with m.p. 58-61.

EXAMPLE 'LXXV 1- (3-Bromopropyl) -1-Ethoxycarbonyl-Z-Indanone To astirred solution of 1,3-dibromopropane (175 m1.) and ethanol (250 ml.)is added dropwise a solution of 1- ethoxycarbonyl-Z-indanone (51 g.) andsodium hydroxide g.) in 500 ml. of ethanol and 200 ml. of water. Thesolution is refluxed for 5 hours and cooled. The bottom layer isseparated and the upper layer is diluted with water and extracted withtwo 100 ml. portions of carbon tetrachloride. The combined lower layerswere washed with 5% aqueous sodium hydroxide and water then concentratedand distilled to give, after a small forecut, the title product (40.3g.) with b.p. 155l65 at 0.5 mm.

EXAMPLE LXXVI l-Ethoxycarbonyl-1,3-Propano-2-Indanone To a stirredmixture of benzene (400 ml.) and sodium hydride (5.3 g. of a 57%suspension in Nujol), which is free of Nujol, is added dropwise, underdry nitrogen, 1- (3-bromopropy1)-1-ethoxycarbonyl-Z-indanone (39.3 g.)in ml. of benzene. The mixture is stirred at room temperature for 18hours. Water is added and the organic layer is separated, washed withaqueous sodium chloride, dried, concentrated and distilled to give aftera small fore cut, 20.5 g. of the title product with b.p. -145 at 0.5

EXAMPLE LXXVII l-Ethoxycarbonyl-1,3-Propano-2-Indanone, Oxime A mixtureof hydroxylamine hydrochloride (2.1 g.), sodium acetate (2.5 g.), water(10 ml.), ethanol (40 ml.) and l-ethoxycarbonyl-1,3-propano-2-indanone(2.5 g.) is heated quickly to its reflux temperature and kept at refluxfor 5 minutes. The mixture is diluted with water and extracted withether. The ether extracts are dried and concentrated to give an oil.Chromatography of the oil on activity III alumina gives, with elutionwith benzene, 2.0 g. of oil which, when triturated withethyl-acetateheptane and filtered, gives 1.20 g. of the title productwith m.p. 118-119".

EXAMPLE LXXVIII 10-Amino-6,7,8,9-Tetrahydro-5,9-Methano6g-Benzocycloheptene-S-methanol A mixture ofl-ethoxycarbonyl-1,3-propano-2-indanone Oxime (1.9 g.) and lithiumaluminum hydride 1.6 g.) and 100 ml. of tetrahydrofuran is heated at itsreflux temperature under dry nitrogen for 40 hours and allowed to standfor 3 days at room temperature. A few ml. of concentrated aqueousammonia is added and after 15 minutes stirring the mixture is filtered.The filter cake is washed twice with isopropanol containing a littleammonia. The combined filtrates are concentrated to give 1.6 g. of oilwhich when treated with hydrogen chloride in ether and ethanol gives 1.2g. of crystalline hydrochloride salt of the title product with m.p.217-220.

Analysis.'Calculated for C H NOCI: C, 65.12; H, 7.57; N, 5.84. Found: C,64.99; H, 7.80; N, 5.73.

EXAMPLE LXXIX5-Methyl-6,7,8,9-Tetrahydro-5,9'-Methano-5H-Benzocycloheptene-lO-AmineTo a cold (5) mixture of pyridine (50 ml.) and 10-amino-6,7,8,9-tetrahyro-5,9-methano 5g benzocycloheptane-S-methanol,hydrochloride (5.1 g.) is added, in portions, 8.0 g. ofp-toluenesulfonyl chloride in 20 ml. of pyridine. After keeping on icefor 3 hours, 8.0 g. of ptoluenesulfonyl chloride in 20 ml. of pyridineis again added. The resulting solution is allowed to stand overnightthen is poured into ice water and extracted with ether. The etherextracts are Washed with dilute hydrochloric acid, dried andconcentrated to give 11 g. of crude product. Trituration of the crudeproduct with ether and recrystallization from ethyl acetate-heptanegives 8.1 g. of product (A) with m.p. 157-159.

Analysis.-Calculated for C H NO' S C, 63.39; H, 4.71; N, 2.74. Found: C,63.33; H, 5.82; N, 2.43.

A mixture of the ditosylate (A) (4.0 g.), lithium aluminum hydride (1.5g.) and tetrahydrofuran is allowed to stir at room temperature for 1hour under nitrogen then is refluxed overnight. Four m1. of water isadded and the mixture is filtered. The collected solid is treated withdilute hydrochloric acid and extracted with ether. The ether extractsare combined with the filtrate of above and concentrated to give an oilysolid (3.4 g.) Crystallization of the solid from ethanol-water gives 1.4g. of product (B) with m.p. 173175.

Analysis.-Calculated for C H NO S: C, 70.36; H, 6.79; N, 4.10. Found: C,70.29; H, 6.65; N, 4.39.

Sodium metal (2.8 g.) is dissolved in a solution of naphthalene (15.4g.) and dimethoxyethane (130 ml.) under a nitrogen atmosphere withstirring. After 1.5 hours, product (B) (4.6 g.), in 45 ml. ofdimethoxyethane, is added and the mixture is stirred for 2 hours. Water(1 ml.)

is added and the mixture concentrated. The residue is dis-.

solved in ether-water and the ether separated. The ether layer isextracted with dilute hydrochloric acid. The acid' layer is basifiedwith concentrated sodium hydroxide and extracted with ether and dried.Addition of ethereal hydrogen chloride gives 2.3 g. of the hydrogenchloride salt of the title product with m.p. 225-227 which is collectedby filtration.

Analysis.Calculated for C H NCl AH Oz C, 68.41; H, 8.16; N, 6.14. Found:C, 68.62; H, 8.10; N, 5.92.

EXAMPLE LXXX Resolution of 5,6,7,8,9,10,11,12'Octahydro3-Methoxy-5ot-Methyl- ,1 l-Methanobenzocyclodecen-13,8-Amine Part A.A solution ofracemic 5,6,7,8,9,10,11,12octahydro 3 methoxy5u-methyl-5,1l-methanobenzocyclodecen-13fl-amine (83 g.) in 200 ml. ofmethanol is added to a solution of d-tartaric acid (57 g.) in 500 ml. ofmethanol. The solution is diluted to 1 liter and allowed to stand for 2days. Filtration gives 83.5 g. of salt with m.p. 200 208 dec. Threerecrystallizations of this salt from methanol give 21 g. of opticallypure tartrate salt with m.p. 213215. This is converted to optically purebase by treatment of the salt with dilute sodium hydroxide andextraction with ether. Exactly /2 of the dried ether extracts (225 ml.)are treated with 15 ml. of ethanol and acidified with ethereal hydrogenchloride. Filtration gives 5.8 g. of the hydrochloride salt of the plusrotating enantiomorph with m.p. 234237.

Analysis.-Calculated for C H NOCl, [a] =+46I C, 69.01; H, 8.86; N, 4.73.Found: C, 68.90; H, 9.10; N, 4.42.

Part B.--The mother liquors of the tartrate crystallization of above areconcentrated and the residue is converted to base by treatment withdilute aqueous sodium hydroxide and extraction with ether. Removal ofthe ether gives 58 g. of base which is dissolved in methanol and treatedwith 38 g. of l-tartaric acid in methanol. The final solution has avolume of 800 ml. Filtration after 4 days of standing gives 41.3 g. oftartrate salt with m.p. 204- 209 dec. Two recrystallizations of thissalt give optically pure tartrate salt with m.p. 216218. Conversion tooptically pure base and subsequently hydrogen chloride salt as in part Ayields 6.0 g. of hydrochloride salt of the minus rotating enantiomorphwith m.p. 234-237 and [a] =46.0.

AnaIysis.-Calculated for C H NOCI: C, 69.01 H, 8.86; N, 4.73. Found: C,68.63; H, 9.10; N, 4.35.

EXAMPLE LXXXI (+)-l3,6-Amino-5,6,7,8,9,10,11,12-Octahydro-5u-Methyl5,11-Methanobenzocyclodecen-3 -ol The second half of the etherealsolution of optically pure plus rotating base described in Example LXXX,part A is concentrated to give 6.5 g. of base. This is treated with 100ml. of 48% aqueous hydrogen bromide and heated at reflux under drynitrogen for /2 hour then concentrated. The residual oil is crystallizedfrom water to give 5.4 g. of hydrogen bromide salt of the title productwith m.p. 268-272 and [a] =+41.4-.

Analysis.Calculated for: C H NOBr- AH O: C, 58.09; H, 7.46; N, 4.23.Found: C, 58.20; H, 7.61; N, 4.23.

34 ()13fl-Arnino-5,6,7,8,9,10,1l,12-Octahydro-5ot-Methyl-5,11-Methanobenzocyclodecen-3-ol In the same manner as described for thepreparation of the plus rotating isomer, from the ethereal solution ofminus rotating base described in Example LXXX, part B there is obtained5.5 g. of hydrogen bromide salt of the title product with m.p. 269271and [a] -=41.7.

Analysis.-Calculated for C H NOBr- AH O: C, 58.09; H, 7.46; N, 4.23.Found: C, 58.47; H, 7.41; N, 4.26.

EXAMPLE LXXXII 13 3-(Dimethylamino)-5,6,7,8,9,10,1 l, 12-Octahydro-5u-Methyl-5,11-Methanobenizocyclodecen-3-ol A solution of5,6,7,8,9,10,11,12-octahydro-3-methoxy- N,N,5a-trimethyl 5,11methanobenzocyclodecen 13 8- amine, hydrochloride (5.0 g.) in ml. of 48%hydrobromic acid is heated at reflux under dry nitrogen for 20 minutesthen concentrated. The residue is crystallized from ethanol-ether togive 4.4 g. of the hydrobromide salt of the title product with m.p.243245 AnaIysis.-Calculated for C H NOBr: C, 61.01; H, 7.96; N, 3.95.Found: C, 61.06; H, 8.10; N, 3.85.

EXAMPLE LXXXIII 5,6,7,8,9,10,11,12 Octahydro 3 Methoxy-N,N,5a-Trimethyl5,11 Methanobenzocyclodecen 13fi-Amine N-Oxide To a cold (0) solution of5,6,7,8,9,10,11,12-octahydro- 3 methoxyN,N,5a-trimethyl-5,1l-methanobenzocyclodecen-13fl-amine (1.5 g.) in 20ml. of dry tetrahydrofuran is added 1.0 g. of meta chloroperbenzoic acidin 10 ml. of tetrahydrofuran. The solution is stirred at 0 to 10 for 30minutes. Two ml. of a saturated solution of hydrogen chloride in ethanolis added. After crystallization occurs, 30 ml. of ether is added and themixture is filtered to give 1.7 g. of the hydrogen chloride salt of thetitle product with m.p. 170-173 dec.

AnaIysis.-Calculated for C I-l NO Cl: C, 67.13; H, 8.90; N, 4.13. Found:C, 66.61; H, 9.04; N, 3.98.

6,7,8,9,-Tetrahydro-N,S-Dimethyl-5,9-Methan0-5 I;I Benzo cyclohepten- 1O-Arnine In a manner analogous to that described in Example XXXVII forthe preparation of 6,7,8,9,10,11-hexahydro- 3-methoxy N,50t dimethyl5,10 methano-SE-benzocyclononen-12wamine from 1.1 g. of6,7,8,9-tetrahydro-5- methyl 5,9 methano SE-benzocyclo-hepten-IO-aminethere is obtained 0.90 g. of the hydrogen chloride salt of the titleproduct with m.p. 289-290".

Analysis.-Calculated for: C H NCI: C, 70.72; H, 8.48; N, 5.89. Found: C,70.40; H, 8.59; N, 5.93.

EXAMPLE LXXXV 1-(4-Bromo)-l-Ethoxycarbonyl-2-Indanone In a manneranalogous to that described in Example LXXV for the preparation of 1 (3bromopropyl)-1- ethoxycarbonyl-2-indanone, from 51 g. ofl-ethoxy-carbonyl-2-indanone there is obtained 41 g.. of the titleproduct with hp. 170 at 0.4 mm.

EXAMPIJE LXXXVI 1-Ethoxycarbonyl-1,3-B utano-2-Indanone In a manneranalogous to that described in Example LXXVI for the preparation ofl-ethoxycarbonyl-1,3-propano-2-indanone, from 45 g. of1-(4-bromo)-1-ethoxycarbonyl-Z-indanone there is obtained 14.5 g. of thetitle product with b.p. at 0.4 mm.

35 EXAMPLE LXXXVII l-Ethoxycarbonyl-1,3-Butano-2-Indanone, Oxime In amanner analogous to that described in Example LXXVII for the preparationof 1-ethoxycarbonyl-1,3- propano-Z-indanone, oxime, from 11 g. ofl-ethoxy-carbonyl-1,3-butano-2-indanone there is obtained 5.5 g. of thetitle product with m.p. l22-4.

EXAMPLE LXXXVIII 11-Amino-5,6,7,8,10-5,10-Methano-Benzocyclooctene-S-Methanol In a manner analogous to that described in Example LXXVIII forthe preparation of 10-amino-6,7,8,9-tetrahydro-5,9-methano-5Ebenzoclycloheptene-S-methanol, from 6.6 g. ofl-ethoxycarbonyl-1,3-butano-2-indanone, oxime there is obtained 4.1 g.of the title product as the hydrogen chloride salt with m.p. 197-200.

Analysis.-Calculated for C H NOCI: C, 66.26; H, 7.94; N, 5.52. Found: C,66.40; H, 8.13; N, 5.80.

EXAMPLE LXXXIX5,6,7,8,9,l-Hexahydro-11-Methylamino-5,IO-Methanobenzocyclooctene-S-MethanolIn a manner analogous to that described in Example XXXVII for thepreparation of 6,7,8,9,10,11-hexahydo-3- methoxyN,5a-dimethyl-5,10-methano-H-benzocyclononen-IZa-amine, from 3.0 g. of11-amino-5,6,7,8,10-5,10- methano-benzocyclooctene-S-methanol there isobtained 1.9 g. of the title product as the hydrogen chloride salt withm.p. 275276.

Analysis.--Calculated for C 5H NOCl: C, 67.27; H, 8.28; N, 5.23. Found:C, 67.38; H, 8.46; N, 5.19.

EXAMPLE XC11-Dimethylamino-5,6,7,8,9,10-Hexahydro-S,IO-Methanobenzocyclooctene-S-MethanolIn a manner analogous to that described in Example LXIV for thepreparation of 5,6,7,8,9,10-hexahydro-3- methoxy N,5udimethyl-5,9-methanobenzocyclooctenellfi-amine, from 1.3 g. of5,6,7,8,9,10-hexahydro-1lmethylamino5,10-methanobenzocyclooctene-S-methanol 1.25 g. of the title product asthe hydrogenchloride salt, m.p. 243-4.

Analysfs.Calculated for C H NOCI: C, 68.19; H, 8.58; N, 4.97. Found: C,67.97; H, 8.67; N, 4.50.

EXAMPLE XCI To prepare:I-(S-bromopentyl)-6,7-dimethoxy-1-methyl-Z-tetralone react 6,7dimethoxy-l-methyLZ-tetralone with 1,5-dibromopentane as taught inExample I.

To prepare: l-allyl-l (4-chlorobutyl)-7-methoxy-2-tetralone react1-allyl-7-methoxy-2-tetralone with 1-bromo-4- chlorobutane as taught inExample I.

To prepare: 7 fluoro-l-(S-bromopentyl)-1-methyl-2- tetralone react7-fiuoro-1-methyl-2-tetralone with 1,5-dibromopentane as taught inExample 1.

EXAMPLE XCII To prepare: 5,6,7,8,9,10,11,12 octahydro-2,3-dimethoxy 5methyl-5,11-methanobenzocyclodecen-13-one treat 1(S-bromopentyl)-6,7-dimethoxy-l-methyl-Z-tetralone with sodium hydrideas taught in Example X.

To prepare: 5 allyl6,7,8,9,10,l1-hexahydro-3-methoxy-5,10-methano-SE-benzocyclononen-12-onetreat 1- allyl-1-(4-chlorobutyl)7-methoxy-2-tetralone with sodiumhydride as taught in Example X.

To prepare: 3 fluoro 5,6,7,8,9,10,11,12-octahydro-5- methyl 5,11methanobenzocyclodecen-13-0ne treat 7- fluoro 1 (5bromopentyl)1-methy1-2-tetralone with sodium hydride as taught inExample X.

36 EXAMPLE xcnr 5,6,7,8,9,10,1l,l2-Octahydro-2,3-DimethoXy-5-Methyl- 5,1l-Methano-Benzocyclodecen-13-Amine Using a procedure analogous to thatdescribed in Example XXVII(A) for the preparation of 6,7,8,9,l0,l1-hexahydro 3-methoXy-5-methyl-5,10 methano-5fl-benzocyclononen-lZ-aminefrom 5.2 g. of 5,6,7,8,9,10,11,12- octahydro 2,3dimethoxy-5-methyl-5,1l-methano-benzocyclodecen-13-one, oxime there isobtained 4.17 g. of the title product which is converted to the hydrogenchloride addition salt, mp. 281-283 Analysis.Calculated for C H O NCl:C, 66.40; H, 8.67; N, 4.30. Found: C, 66.27; H, 8.81; N, 4.23.

EXAMPLE XCV5-Allyl-6,7,8,9,10,11-Hexahydro-3-MethoXy-5,IO-Methano-SE-Benzoclyclononen-12-AmineUsing a procedure analogous to that described in Example XXVII(A) forthe preparation of 6,7,8,9,10,11- hexahydro3-methoxy-5-methyl-5,IO-methano-SH-benzocyclononen-12-amine, from 13.3g. of 5-allyl-6,7,8,9,l0,1lhexahydro 3 methoxy-5,10-methano-5I-benzocyclononen-l2-one, oxime there is obtained 6.3 g. of the titleproduct which is converted to the fumaric acid addition salt, m.p.219220.

Analysis. Calculated for C H NO C, 68.19; H, 7.54; N, 3.62. Found: C,68.42; H, 7.78; N, 3.99.

EXAMPLE XCVI 3-Fluoro-5,6,7,8,9,10,11,12-Octahydro-5ot-Methyl-5,11-

Methanobenzocyclodecen-13 fl-Amine Using a procedure analogous to thatdescribed in Example XXVIHA) for the preparation of 6,7,8,9,10,l1-hexahydro 3 methoxy-S-methyl-S,IO-methano-SE-benzocyclononen-lZ-amine,from 14.1 g. of 3-fluoro-5,6,7,8, 9,10,11,12-octahydro-5-methyl 5,11methano-benzocyclodecen-13-one, oxime there is obtained 10.5 g. of thetitle product which is converted to the fumaric acid addition salt (8g.) of the title product, m.p. 218-220".

Analysis.-Calculated for: C H FNO C, 66.10; H, 7.21; N, 3.85. Found: C,65.80; H, 7.26; N, 3.58.

EXAMPLE XCVII 3-Methoxy-5ot-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,1l-Methanobenzocyclodecen-13a-Amine From the mother liquors remainingafter the isolation of the product of Example XXXV, 3-methoxy-5a-methyl-5,6,7,8,9,l0,11,12 octahydro 5,1l-methano-benzocyclodecen-13,8-amine,there is obtained by following a pro cedure analogous to that describedin Example XXXIV part C for the isolation of5,6,7,8,9,l0-hexahydro-3-methoxy 50c methyl 5,9methano-benzocycloocten-l1,8- amine, hydrochloride, the title product,m.p. 207208.

37 EXAMPLE XCVIII 3 -Methoxy-N,5a-Dimethyl-5,6,7,8,9, 10,11,12-Octahydro- 5,1 1-Methanobenzocyclodecen-13 a-Amine In a manneranalogous to that described in Example XXXVII for the preparation of6,7,8,9,10,11-hexahydro- 3 methoxy-N,5a dirnethyl5,10-methano-5g-benzocyclononen-12a-amine there is obtained from3-methoxy- 5a methyl5,6,7,8,9,10,l1,12-octahydro-5,1l-methanobenzocyclodecen-Ba-amine thetitle product with an NMR analysis having an N-CH signal at 5:2.48p.p.m. (free base).

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:

1. A method for inducing analgesia in warmblooded animals whichcomprises administering to warmblooded animals a pharmaceuticallyeffective amount of a compound of the structure 3. A method for inducinganalgesia as defined in claim 1 wherein the compound administered is12fi-amino-6,7, 8,9,10,11 hexahydro 5oz methyl-ilO-methano-SE-benzocyclononen-3-ol.

4. A method for inducing analgesia as defined in claim 1 wherein thecompound administered is 5a-ethyl-6,7,8,9, 10,11 hexahydro 3methoxy-S,IO-methano-SE-henzocyclononen-lZfi-amine.

5. A method for inducing analgesia as defined in claim 1 wherein thecompound administered is 12fi-amino-6,7, 8,9,10,11 hexahydro 5aethyl-5,IO-methano-SE-benzocyclononen-3-ol.

6. A method for inducing analgesia as defined in claim 1 wherein thecompound administered is 3-methoxy-5u methyl 5,6,7,8,9,10,11,12octahydro-5,11-methanobenzocyclodecen- 1 SIB-amine.

7. A method for inducing analgesia as defined in claim 1 wherein thecompound administered is 13,3-amino-5otmethyl 5,6,7,8,9,10,11,12octahydro 5,11 methanobenzocyclodecen-3-ol.

8. A method for inducing analgesia as defined in claim 1 wherein thecompound administered is ()-13,8-amino- 5,6,7,8,9,10,11,12 octahydro 5amethyl-5,11-methanobenzocyclodecen-3-ol.

References Cited Mitsuhasi et al.: Chem. Pharm. Bulletin (Tokyo), 1876-87 (1970).

STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.

